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Pharmacokinetics of chlormadinone acetate following single and multiple oral dosing of chlormadinone acetate (2 mg) and ethinylestradiol (0.03 mg) and elimination and clearance of a single dose of radiolabeled chlormadinone acetate
Contraception 74 (2006) 239 – 244
Original research article
Pharmacokinetics of chlormadinone acetate following single and multiple oral dosing of chlormadinone acetate (2 mg) and ethinylestradiol (0.03 mg) and elimination and clearance of a single dose of radiolabeled chlormadinone acetate Rolf Terlindena, Heinz Uragga, Karin Gfhlerb, Christa Kneipa,4 a Department of Pharmacokinetics, Gru¨nenthal GmbH, D-52099 Aachen, Germany Department of Clinical Pharmacology, Gru¨nenthal GmbH, D-52099 Aachen, Germany Received 16 August 2005; revised 14 March 2006; accepted 20 March 2006
b
Abstract Background: Published data on pharmacokinetic parameters for chlormadinone acetate (CMA) are in part contradictory, especially with regard to terminal half-life (t 1/2,z ). Materials and Methods: Single and multiple doses of CMA (2 mg) and ethinylestradiol (EE; 0.03 mg) were administered to healthy female volunteers for six menstrual cycles. Plasma concentrations of CMA and EE were determined by gas chromatography–mass spectrometry. Single-dose and steady-state pharmacokinetic parameters were calculated. In a separate study, healthy female volunteers were given a single 2-mg dose of radiolabeled CMA. Concentrations of radioactivity in fecal and urine samples were determined via liquid scintillation. Excretion of total radioactivity was calculated as percentage of administered dose. Results: Eighteen women completed the repeated-dose study. Peak plasma concentrations for CMA and EE were reached within 1 and 2 h after taking the study drug. Peak plasma concentrations of CMA were ~1600 pg/mL after single-dose administration and 2000 pg/mL after multiple dosing. CMA and EE showed linear pharmacokinetics throughout six cycles, with constant trough values of ~ 400 – 500 pg/mL for CMA and 20 – 40 pg/mL for EE. Mass balance factors were 1.2 – 1.4 for CMA and 1.6 – 1.7 for EE, and accumulation factors were 1.7 – 2 for CMA and 1.7–1.8 for EE. Mean t 1/2,z of CMA was approximately 25 h after single dosing and 36 – 39 h at steady state. In the excretion balance study, mean dose of CMA recovered was 87.3F6.4%, with urinary and fecal excretion accounting for 45% and 42%, respectively. Conclusions: The pharmacokinetics of CMA and EE is linear after multiple dosing and remains stable during long-term administration, once steady state is reached. The t 1/2,z of CMA was 36–39 h after multiple dosing, which is considerably shorter than the 80 h often quoted in the literature. D 2006 Elsevier Inc. All rights reserved. Keywords: Chlormadinone acetate; Ethinylestradiol; Pharmacokinetics
1. Introduction After the first oral contraceptives became available in the United States in 1960 [1], concern about adverse reactions led to a reduction in estrogen dose and the introduction of new progestogens [2–5]. In 1998, a monophasic combination of 2 mg of chlormadinone acetate (CMA), a synthetic progestogen, and 0.03 mg of ethinylestradiol (EE), a synthetic estrogen, was approved in Germany as an oral contraceptive under the trade name BelaraR, and its reliable contraceptive efficacy has been described in detail [6,7]. 4 Corresponding author. 0010-7824/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2006.03.011
In contrast to most progestogens, which are derived from nortestosterone, CMA is a derivative of 17a-hydroxyprogesterone. It is a potent progestogen with antiandrogenic activity but shows no anabolic or androgenic effect. Substances of this class compete with androgens at target receptors in skin and hair, thus improving acne, seborrhea, alopecia and hirsutism [8]. The efficacy of CMA in an oral contraceptive in the treatment of acne in women has also been demonstrated in a comparative study [9]. Whereas the pharmacokinetic properties of EE are well characterized [10–16], pharmacokinetic data on CMA dates mainly from the 1970s when sensitive and specific assays
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for CMA were not available [17]. Moreover, at that time, there was no consensus on how to calculate and present pharmacokinetic parameters. Since then, only one singledose pharmacokinetic study of an oral combination of CMA and EE has been published [18]. This recent study contradicted earlier findings, particularly regarding the elimination times of CMA. We therefore investigated the pharmacokinetics of CMA and EE after administration of single and multiple doses of a tablet containing 0.03 mg EE and 2 mg CMA to 18 healthy women of childbearing age. A small additional study of 4 healthy volunteers with radiolabeled CMA aimed to provide further information on the excretion and plasma pharmacokinetics of total radioactivity. 2. Materials and methods Two open-label, single-center studies were performed: a comprehensive study of the pharmacokinetics of single and multiple doses of CMA in combination with EE and a study to determine the excretion and plasma kinetics of a single dose of radiolabeled CMA alone. In the repeated-dose study, female volunteers aged 18–24 years and with a body weight of 50–85 kg were to be included if they were deemed healthy after laboratory and electrocardiogram screening and after a thorough medical and gynecological examination. The main exclusion criteria were pregnancy and concomitant medication or physical conditions that might interfere with the objectives of the study or enhance the risk of adverse drug reactions to the oral contraceptive combination. In the CMA excretion study, sterilized females aged 30–45 years and within 15% of ideal body weight were to be included. All volunteers in both studies gave written informed consent prior to inclusion. Both studies were submitted to ethics committees for approval and were conducted according to good clinical practice guidelines and the Declaration of Helsinki (Hong Kong Amendment of 1989). 2.1. Conduct and analytical methods of the repeated-dose study This study lasted approximately 8 months (two medication-free run-in cycles and six medication cycles) for individual volunteers (i.e., eight menstrual cycles). Study treatment consisted of 2 mg CMA with 0.03 mg EE in a single tablet (equivalent to 1 tablet BelaraR) administered orally in the morning. Volunteers received a single dose of study drug on Day 21 of the first cycle (Cycle 2), followed by a further medication-free cycle (Cycle 1) and six cycles with multiple intakes of study drug (Cycles +1 to +6). During the six-cycle period of multiple dosing, each cycle included 21 days of daily intake followed by a 7-day drug-free interval. Throughout the study, adverse events, any concomitant medication and bleeding behavior were recorded, and laboratory parameters and vital signs were monitored.
Blood samples of 12 mL each were drawn from a cubital vein after overnight fasting and collected in heparinized tubes for pharmacokinetic evaluation at the following times: Day 21 of Cycles 2, +1, +3 and +6 Day 10 of Cycle +1 Days 15, 17 and 19 of Cycles +1, +3 and +6
15 min before intake and 0.5, 1, 1.5, 2, 3, 5, 8, 11, 16, 24, 32, 48 and 56 h thereafter 15 min before intake and 0.5, 1, 1.5, 2 and 4 h thereafter 5 min before intake
Blood samples were centrifuged at approximately 2700g for 10 min, and plasma samples were pipetted into two identically labeled vials for storage at V 208C. Additional samples were drawn to measure endogenous sex steroids and binding proteins as well as to test for pregnancy. Both EE and CMA were determined in plasma with a validated analytical method using derivatization and capillary gas chromatography–mass spectrometry (GC–MS) with negative chemical ionization. CMA was derivatized with pentafluorobenzylhydroxylamine, and EE was derivatized with 3,5-bis-(trifluoromethyl)-benzoylchloride. Internal standards were megestrol acetate for CMA and 2 H4-ethinylestradiol (d4-EE) for EE. Using 1 mL of plasma, limits of quantification were 100 pg/mL for CMA and 10 pg/mL for EE, with calibration ranges of 100–2500 and 10–500 pg/mL, respectively. All measurements were suitably calibrated and subjected to quality control. Pharmacokinetic evaluations were performed on the first 18 of the 22 volunteers eligible for analysis using a noncompartmental method. The area under the (plasma concentration) curve (AUC) was calculated according to the equation of Gibaldi and Perrier [19]: AUC0–t (AUC between t =0 and t) was calculated by the trapezoidal rule, and AUCt–l (AUC between t and infinity) was extrapolated using the terminal half-life of elimination (t 1/2,z ), which was calculated using a log-linear regression analysis [20]. Since concentrations could usually be measured up to 16 h only for EE, AUC0–24 was derived from the extrapolated AUC. The rate of absorption after the first and last administration was characterized by the time (T max) to attain the maximum plasma concentration (C max). Mass balance factor (R 1), accumulation factor (R 2) and theoretical accumulation factor (R theo) were calculated according to the following formulae [21]: R1 ¼ AUCss;md =AUCsd R2 ¼ AUCss;md =AUC024;sd Rtheo ¼ 1=ð1 2e Þ; where ss, sd and md indicate steady state, single dose and multiple doses, respectively, and e = s/t 1/2,z , where s is dosing
R. Terlinden et al. / Contraception 74 (2006) 239 – 244
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Fig. 1. Mean (n = 18) plasma concentrations of CMA after single and multiple dosing (Day 21 of the treatment cycle) of the oral contraceptive.
Fig. 2. Mean (n = 18) plasma concentrations of EE after single and multiple dosing (Day 21 of the treatment cycle) of the oral contraceptive.
interval (which is 24 h in this case). For CMA, only a small fraction of the dose is represented by the AUC dominated by the terminal half-life. Therefore, R theo was calculated using the beffectiveQ half-life (t 1/2,eff ), defined as t 1/2,eff = ln(2)mean residence time according to Gibaldi and Perrier [22], instead of t 1/2,b . Single- and multiple-dose pharmacokinetic results were compared descriptively.
intervals thereafter: 0–2, 2–4, 4– 6, 6–8, 8–12, 12–24, 24–48, 48–72, 72–96, 96–120, 120–144, 144–168, 168–192, 192–216, 216–240, 240–264 and 264–288 h. Feces were collected as voided into preweighed, labeled containers and analyzed in 24-h periods for up to 288 h. Total radioactivity was determined in urine by liquid scintillation analysis using a Packard TR1600 automatic counter equipped with an automatic standardization system. Feces were combusted in a Packard Tri-Carb 306 Automated Sample Oxidizer prior to scintillation analysis. Cumulative excretion of total radioactivity in urine and feces is presented descriptively as the mean (FSD) of the percentage of administered dose by time interval.
2.2. Conduct and analytical methods of the CMA excretion study After a screening period of up to 14 days, 4 subjects were admitted to the clinic on the evening before dosing. Volunteers fasted from 2300 h on the evening before dosing until 4 h after dosing. Standardized meals were served thereafter. Volunteers were monitored for laboratory parameters and vital signs; adverse events and concomitant medications were recorded. Volunteers received a single oral dose of 2 mg (1.96 MBq) 14 C-CMA dissolved in 1 mL ethanol and dispensed in two separate gelatin capsules. The radiation dose was prepared in compliance with the International Commission of Radiological Protection Guidelines of 1992 [23]. Urine samples were collected in preweighed and labeled containers before taking the study drug and at the following
3. Results 3.1. Single and multiple oral administration of 2 mg CMA and 0.03 mg EE The study was completed by 19 volunteers. Three women dropped out: one because of pregnancy before taking any study medication, one because of weight gain and one because of intracyclic bleeding. The mean age of those who completed the study was 31.6 years, and the mean body weight was 61.0 kg. During
Table 1 Mean (FSD) pharmacokinetic parameters of CMA (Day 21 of the treatment cycle) after single- and multiple-dose administration of the oral contraceptive combination (n = 18) Parameter
Single dose, Cycle 2
Multiple doses, Cycle +1
Multiple doses, Cycle +3
Multiple doses, Cycle +6
AUC (pgd h/mL) AUC0–24/AUCss (pgd h/mL) C max/C ss,max (pg/mL) T max/Tss,max (h) MRT (h) C ss,av (pg/mL) R1 R2 t 1/2,z (h)
14,403F4392 9685F2468 1597.3F458.2 1.61F0.37 24.5F10.7 – – – 25.3F9.8
– 19,361F5505 2213.6F604.0 1.61F0.50 – 807F229 1.41F0.38 2.02F0.40 36.5F8.5
– 15,829F3802 2006.6F508.1 1.47F0.50 – 660F158 1.17F0.34 1.69F0.44 39.1F13.4
– 15,944F3338 2058.6F473.5 1.40F0.42 – 664F139 1.17F0.28 1.70F0.38 38.1F15.1
AUC0–24, AUC between t = 0 and t = 24; C max, peak concentration; C ss,max, peak concentration at steady state; T max, time to maximum concentration; Tss,max, time to maximum concentration at steady state; MRT, mean residence time; C ss,av, average steady-state concentration; R 1, mass balance factor; R 2, accumulation factor; t 1/2,z , terminal half-life of elimination.
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Table 2 Mean (FSD) pharmacokinetic parameters of EE (Day 21 of the treatment cycle) after single- and multiple-dose administration of the oral contraceptive combination (n = 18) Parameter
Single dose, Cycle 2
Multiple doses, Cycle +1
Multiple doses, Cycle +3
Multiple doses, Cycle +6
AUC (pgd h/mL) AUC0–24/AUCss (pgd h/mL) C max/C ss,max (pg/mL) T max/Tss,max (h) MRT (h) C ss,av (pg/mL) R1 R2 t 1/2,z (h)
680F277 600F212 83.6F31.5 1.47F0.36 10.4F4.4 – –
– 1051F563 123.9F36.4 1.92F2.33 – 43.8F23.5 1.69F0.94 1.87F0.98 13.1F5.0
–
– 1006F313 129.8F40.1 1.31F0.39 – 41.9F13.0 1.63F0.58 1.80F0.53 14.2F5.3
7.6F3.7
972F330 130.6F43.0 1.11F0.37 – 40.5F13.8 1.57F0.60 1.73F0.57 12.3F4.7
AUC0–24, AUC between t = 0 and t = 24; C max, peak concentration; C ss,max, peak concentration at steady state; T max, time to maximum concentration; Tss,max, time to maximum concentration at steady state; MRT, mean residence time; C ss,av, average steady-state concentration; R 1, mass balance factor; R 2, accumulation factor; t 1/2,z , terminal half-life of elimination.
the whole study, there were only two missed doses, and all examinations were performed on schedule. No serious or unexpected adverse events were reported. The most common adverse event was headache, mostly rated as mild or moderate. This adverse event was consistently spread over medication-free run-in cycle and medication cycles. Other common adverse events were dysmenorrhea, nausea, breast pain and vaginal discharge. In most cases, the severity was rated as mild to moderate. These adverse events are among those most commonly reported during the intake of combined oral contraceptives. No relevant findings were reported in the other safety assessments. According to the protocol, the first 18 women who completed the study were included in the main pharmacokinetic evaluation. The GC–MS technique was highly accurate for quantifying the plasma concentrations of CMA and EE. The average percentage deviation from the nominal value for the 47 calibration curves of CMA was 3.1% at the lowest level and between 0% and 3.3% at the remaining standard concentrations. Interassay accuracy for CMA measurement ranged from 99.1% to 101.8%, and precision ranged from 5.3% to 8.1%. For EE, the average percentage deviation from the nominal value for the 18 calibration curves was 3.3% at the lowest level and between 0.3% and 4% at the remaining standard concentrations. Interassay accuracy for EE measurement ranged from 97.7% to 103.4%, and precision ranged from 3.9% to 8.6% Figs. 1 and 2 show the mean plasma concentration profiles of CMA and EE, respectively, after single and multiple doses of the oral contraceptive combination (2 mg CMA/0.03 mg EE). Pharmacokinetic parameters calculated for CMA and
EE are presented in Tables 1 and 2, respectively. Trough values for both analytes are listed in Tables 3 and 4. Concentrations of CMA could be measured in most subjects up until 32 h after single dosing and up until 56 h (the last sampling point) after multiple dosing. Concentrations of EE could be measured in most subjects until 16 h after single dosing and up until 24–32 h after multiple dosing. Peak plasma concentrations for CMA and EE were reached within 1 and 2 h after taking the study drug. Mean peak plasma concentrations of CMA were approximately 1600 pg/mL after single-dose administration and rose to approximately 2000 pg/mL after multiple dosing. AUC0–24 for CMA increased from 9685 pgd h/mL after single dosing to an AUCss of 16,000–19,000 pgd h/mL after multiple dosing; for EE, it increased from 600 pgd h/mL after single dosing to about 1000 pgd h/mL after multiple dosing. For both CMA and EE, AUCss and C ss,max remained constant throughout the entire six cycles. Accordingly, average trough values of about 400–500 pg/mL for CMA and 20–40 pg/mL for EE were reached at the latest on Day 15 and remained constant throughout the entire study period. For CMA, a mean t 1/2,z of 25 h after single dose and mean t 1/2,z of 36–39 h after multiple doses were determined. For EE, a mean t 1/2,z of 7.6 h after single dose and mean t 1/2,z of 12–14 h after multiple doses were found. R 1 values of 1.2–1.4 for CMA and 1.6–1.7 for EE were calculated. Corresponding R 2 values of 1.7–2 for CMA and 1.7–1.9 for EE were determined.
Table 3 Mean (FSD) trough values for CMA after multiple daily administration of a combination of 2 mg CMA and 0.03 mg EE
Table 4 Mean (FSD) trough values for EE after multiple daily administration of a combination of 2 mg CMA and 0.03 mg EE
Day
Cycle +1 (pg/mL)
Cycle +3 (pg/mL)
Cycle +6 (pg/mL)
Day
Cycle +1 (pg/mL)
Cycle +3 (pg/mL)
Cycle +6 (pg/mL)
10 15 17 19 21
446F103 497F144 513F173 507F197 494F150
– 402F120 402F143 386F123 393F140
– 390F164 381F157 385F116 412F130
10 15 17 19 21
16F4 27F26 30F27 24F22 19F6
– 39F40 43F44 39F45 20F6
– 25F12 21F7 20F8 20F6
3.2. Single-dose study of renal and fecal excretion of CMA The four subjects included in the excretion study were aged between 31 and 40 years and weighed between 47.0 and 74.1 kg.
R. Terlinden et al. / Contraception 74 (2006) 239 – 244 Table 5 Mean (FSD) cumulative excretion of total radioactivity in urine and feces as a percentage of dose (n = 4) Time (h)
Urine
Feces
Total recovery
2 4 6 8 12 24 72 120 144 240 288
0.5F0.4 3.1F1.1 5.3F0.9 6.4F1.4 8.8F1.8 13.4F2.1 30.7F4.2 38.9F4.1 41.4F3.7 45.2F3.8 47.4a
– – – – – – 15.5F15.6 31.6F13.5 35.9F10.9 42.1F8.5 37.4a
0.5F0.4 3.1F1.1 5.3F0.9 6.4F1.4 8.8F1.8 13.4F2.1 46.2F16.7 70.5F14.3 77.3F10.9 87.3F6.4 84.8a
a
n = 2.
Table 5 summarizes renal and fecal excretion of total radioactivity. Two hundred forty hours post dose, the mean dose recovered was 87.3F6.4% (range, 81.0–93.3%). Urinary excretion accounted for 45.2% (range, 40.7– 48.5%) of the dose, and excretion in feces accounted for 42.1% (range, 32.4–52.6%). 4. Discussion In the present study, t 1/2,z of CMA after a single dose was approximately 25 h, and it was approximately 36–39 h during multiple dosing. Because of the higher plasma concentrations of CMA during multiple dosing, CMA was quantifiable up to approximately 56 h, as compared with 38 h after single dosing. Thus, more data points could be used for calculating the terminal regression line, and the value may be more accurate. The single-dose t 1/2,z of CMA in the present study is shorter than the value reported by Chassard et al. [18], although t 1/2,z during multiple dosing is similar. However, the dose in the cited study was five times greater than that in the present study, and hence, CMA concentrations could be quantified for a longer period after dosing, allowing for a more accurate determination of t 1/2,z . The plasma concentrations of CMA were quantified using the same GC–MS method as in the present multiple-dose study. In theory, 90–99% of steady-state concentrations are reached after 3.3–7 half-lives [21]; hence, it would be expected that steady state was reached on average after 5–11 days. Since trough concentrations were not measured before Day 15 (Day 10 for Cycle +1), the present study confirms that steady state is reached at the latest at Day 15, possibly even earlier. Accumulation, as measured by the accumulation factor R 2, was approximately twofold for Cycle +1 with respect to single dose and 1.7 for Cycles +3 and +6. This compares reasonably well with theoretical accumulation factors of 2–2.2. The R 1 values of 1.4 in Cycle +1 and 1.2 in Cycles +3 and +6 suggest that the pharmacokinetics of CMA is linear at this dose and, therefore, that resorption is constant.
243
AUCss, C max and trough values remained constant over the entire study period of 6 months, demonstrating stable, timeindependent pharmacokinetics. In the excretion balance study, the amount excreted by renal and fecal routes was roughly equal. This, together with the relatively long half-life of CMA, is in agreement with enterohepatic recirculation of CMA or its metabolites. Although CMA has been used in oral contraceptives for decades, only two studies of its pharmacokinetic profile have been published in the scientific literature. In the seminal study of the pharmacokinetics of CMA dating from the 1970s [17], radiolabeled CMA was administered as a single intravenous dose. The dose of CMA, however, was not explicitly stated; only the dose of radioactivity was reported (60–90 ACi). The subjects, aged between 34 and 52 years, were hospital patients awaiting a total hysterectomy and were not representative of women who would normally take oral contraceptives. The analytical methods consisted of several extraction steps, followed by thin-layer chromatography and liquid scintillation counting. The validity of these methods, although unknown, seems questionable based on current knowledge. Mean t 1/2,z was 80.1 h for total radioactivity (calculated for five subjects) and 81.8 h for CMA-specific radioactivity (calculated for four subjects). In addition to the unknown validity and presumed low sensitivity and low accuracy of the bioanalytical methods used in the 1970s and the nonrepresentative study population, the small number of subjects and the limited number of data points used to calculate the pharmacokinetic parameters (for t 1/2,z , 4 or 5 points were used) further detract from the reliability of the results. Nevertheless, the long t 1/2,z of over 80 h is still quoted in the literature [24,25]. Chassard et al. [18] investigated the relative bioavailability of two oral doses of CMA (25 mg and 10 mg) after single dosing in 12 healthy women between 18 and 30 years old. The pharmacokinetic parameters were similar for the two formulations, with t 1/2,z at approximately 36 h and T max at 2.5 h. The pharmacokinetics of EE in the present study agreed well with results published in the literature. During multiple dosing, t 1/2,z was around 13 h, which lies within the wide range of 6 to 27 h reported for t 1/2,z of EE [26,27]. In modern oral contraceptives, the dose of EE is low (0.03 mg), making accurate determination of pharmacokinetic parameters difficult. In our study, the lower limit of quantification (10 pg/mL) was reached between 8 and 16 h after administration of a single dose — too soon for an accurate determination of t 1/2,z , accumulation factor or mass balance factor. During multiple dosing, plasma concentrations of EE could be quantified for a longer period, which may explain why the measured t 1/2,z was longer. R 1 and R 2 values for EE were higher than theoretically predicted (R 2 = 1.7–1.9; R theo = 1.2–1.4) but well within the wide range reported in literature [11,28–31]. The overestimation of R 1 and R 2 is not surprising given that, on average, 25% of the AUC and 17% of the AUC0–24 were extrapolated.
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In conclusion, the reliable pharmacokinetic data on CMA in young healthy women obtained in these studies confirm the findings of Chassard et al. [18]. The t 1/2,z after multiple dosing was found to be 36–39 h, which is considerably shorter than the value often presented in the literature (80 h or more) [24,25]. Furthermore, it was demonstrated that the pharmacokinetics of CMA and EE after multiple administrations is well within theoretical predictions, is linear after multiple dosing and, hence, remains stable over extended periods of time once steady state is reached. References [1] Fraser IS. Forty years of combined oral contraception: the evolution of a revolution. Med J Aust 2000;173:541 – 4. [2] Prentice RL, Thomas DB. On the epidemiology of oral contraceptives and disease. Adv Cancer Res 1987;49:285 – 401. [3] Gillum LA, Mamidipudi SK, Johnston SC. Ischemic stroke risk with oral contraceptives. A meta-analysis. JAMA 2000;284:72 – 8. [4] Schildkraut JM, Calingaert B, Marchbanks PA, Moorman PG, Rodriguez GC. Impact of progestin and estrogen potency in oral contraceptives on ovarian cancer risk. J Natl Cancer Inst 2002; 94:32 – 8. [5] Grabrick DM, Hartmann LC, Cerhan JR, et al. Risk of breast cancer with oral contraceptive use in women with a family history of breast cancer. JAMA 2000;284:1791 – 8. [6] Zahradnik HP, Goldberg J, Andreas JO. Efficacy and safety of the new antiandrogenic oral contraceptive BelaraR. Contraception 1998;57: 103 – 9. [7] Curran MP, Wagstaff AJ. Ethinylestradiol/chlormadinone acetate. Drugs 2004;64:751 – 60. [8] Raudrant D, Rabe T. Progestogens with antiandrogenic properties. Drugs 2003;63:463 – 92. [9] Worret I, Arp W, Zahradnik HP, Andreas JO. Acne resolution rates: results of a single-blind, randomized, controlled, parallel phase III trial with EE/CMA (Belara) and EE/LNG (Microgynon). Dermatology 2001;203:38 – 44. [10] Dibbelt L, Knuppen R, Ju¨tting G, Heimann S, Klipping CO, Parikka-Olexik H. Group comparison of serum ethynylestradiol, SHBG and CBG levels in 83 women using two low-dose combination oral contraceptives for three months. Contraception 1991; 43:1 – 21. [11] Kuhnz W, Staks T, Ju¨tting G. Pharmacokinetics of cyproterone acetate and ethinylestradiol in 15 women who received a combination oral contraceptive during three treatment cycles. Contraception 1993;48: 557 – 75. [12] Kuhnz W, Hu¨mpel M, Biere H, Gross D. Influence of repeated oral doses of ethinylestradiol on the metabolic deposition of [13C2]ethinylestradiol in young women. Eur J Clin Pharmacol 1996;50: 231 – 5.
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Original research article
Pharmacokinetics of chlormadinone acetate following single and multiple oral dosing of chlormadinone acetate (2 mg) and ethinylestradiol (0.03 mg) and elimination and clearance of a single dose of radiolabeled chlormadinone acetate Rolf Terlindena, Heinz Uragga, Karin Gfhlerb, Christa Kneipa,4 a Department of Pharmacokinetics, Gru¨nenthal GmbH, D-52099 Aachen, Germany Department of Clinical Pharmacology, Gru¨nenthal GmbH, D-52099 Aachen, Germany Received 16 August 2005; revised 14 March 2006; accepted 20 March 2006
b
Abstract Background: Published data on pharmacokinetic parameters for chlormadinone acetate (CMA) are in part contradictory, especially with regard to terminal half-life (t 1/2,z ). Materials and Methods: Single and multiple doses of CMA (2 mg) and ethinylestradiol (EE; 0.03 mg) were administered to healthy female volunteers for six menstrual cycles. Plasma concentrations of CMA and EE were determined by gas chromatography–mass spectrometry. Single-dose and steady-state pharmacokinetic parameters were calculated. In a separate study, healthy female volunteers were given a single 2-mg dose of radiolabeled CMA. Concentrations of radioactivity in fecal and urine samples were determined via liquid scintillation. Excretion of total radioactivity was calculated as percentage of administered dose. Results: Eighteen women completed the repeated-dose study. Peak plasma concentrations for CMA and EE were reached within 1 and 2 h after taking the study drug. Peak plasma concentrations of CMA were ~1600 pg/mL after single-dose administration and 2000 pg/mL after multiple dosing. CMA and EE showed linear pharmacokinetics throughout six cycles, with constant trough values of ~ 400 – 500 pg/mL for CMA and 20 – 40 pg/mL for EE. Mass balance factors were 1.2 – 1.4 for CMA and 1.6 – 1.7 for EE, and accumulation factors were 1.7 – 2 for CMA and 1.7–1.8 for EE. Mean t 1/2,z of CMA was approximately 25 h after single dosing and 36 – 39 h at steady state. In the excretion balance study, mean dose of CMA recovered was 87.3F6.4%, with urinary and fecal excretion accounting for 45% and 42%, respectively. Conclusions: The pharmacokinetics of CMA and EE is linear after multiple dosing and remains stable during long-term administration, once steady state is reached. The t 1/2,z of CMA was 36–39 h after multiple dosing, which is considerably shorter than the 80 h often quoted in the literature. D 2006 Elsevier Inc. All rights reserved. Keywords: Chlormadinone acetate; Ethinylestradiol; Pharmacokinetics
1. Introduction After the first oral contraceptives became available in the United States in 1960 [1], concern about adverse reactions led to a reduction in estrogen dose and the introduction of new progestogens [2–5]. In 1998, a monophasic combination of 2 mg of chlormadinone acetate (CMA), a synthetic progestogen, and 0.03 mg of ethinylestradiol (EE), a synthetic estrogen, was approved in Germany as an oral contraceptive under the trade name BelaraR, and its reliable contraceptive efficacy has been described in detail [6,7]. 4 Corresponding author. 0010-7824/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2006.03.011
In contrast to most progestogens, which are derived from nortestosterone, CMA is a derivative of 17a-hydroxyprogesterone. It is a potent progestogen with antiandrogenic activity but shows no anabolic or androgenic effect. Substances of this class compete with androgens at target receptors in skin and hair, thus improving acne, seborrhea, alopecia and hirsutism [8]. The efficacy of CMA in an oral contraceptive in the treatment of acne in women has also been demonstrated in a comparative study [9]. Whereas the pharmacokinetic properties of EE are well characterized [10–16], pharmacokinetic data on CMA dates mainly from the 1970s when sensitive and specific assays
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for CMA were not available [17]. Moreover, at that time, there was no consensus on how to calculate and present pharmacokinetic parameters. Since then, only one singledose pharmacokinetic study of an oral combination of CMA and EE has been published [18]. This recent study contradicted earlier findings, particularly regarding the elimination times of CMA. We therefore investigated the pharmacokinetics of CMA and EE after administration of single and multiple doses of a tablet containing 0.03 mg EE and 2 mg CMA to 18 healthy women of childbearing age. A small additional study of 4 healthy volunteers with radiolabeled CMA aimed to provide further information on the excretion and plasma pharmacokinetics of total radioactivity. 2. Materials and methods Two open-label, single-center studies were performed: a comprehensive study of the pharmacokinetics of single and multiple doses of CMA in combination with EE and a study to determine the excretion and plasma kinetics of a single dose of radiolabeled CMA alone. In the repeated-dose study, female volunteers aged 18–24 years and with a body weight of 50–85 kg were to be included if they were deemed healthy after laboratory and electrocardiogram screening and after a thorough medical and gynecological examination. The main exclusion criteria were pregnancy and concomitant medication or physical conditions that might interfere with the objectives of the study or enhance the risk of adverse drug reactions to the oral contraceptive combination. In the CMA excretion study, sterilized females aged 30–45 years and within 15% of ideal body weight were to be included. All volunteers in both studies gave written informed consent prior to inclusion. Both studies were submitted to ethics committees for approval and were conducted according to good clinical practice guidelines and the Declaration of Helsinki (Hong Kong Amendment of 1989). 2.1. Conduct and analytical methods of the repeated-dose study This study lasted approximately 8 months (two medication-free run-in cycles and six medication cycles) for individual volunteers (i.e., eight menstrual cycles). Study treatment consisted of 2 mg CMA with 0.03 mg EE in a single tablet (equivalent to 1 tablet BelaraR) administered orally in the morning. Volunteers received a single dose of study drug on Day 21 of the first cycle (Cycle 2), followed by a further medication-free cycle (Cycle 1) and six cycles with multiple intakes of study drug (Cycles +1 to +6). During the six-cycle period of multiple dosing, each cycle included 21 days of daily intake followed by a 7-day drug-free interval. Throughout the study, adverse events, any concomitant medication and bleeding behavior were recorded, and laboratory parameters and vital signs were monitored.
Blood samples of 12 mL each were drawn from a cubital vein after overnight fasting and collected in heparinized tubes for pharmacokinetic evaluation at the following times: Day 21 of Cycles 2, +1, +3 and +6 Day 10 of Cycle +1 Days 15, 17 and 19 of Cycles +1, +3 and +6
15 min before intake and 0.5, 1, 1.5, 2, 3, 5, 8, 11, 16, 24, 32, 48 and 56 h thereafter 15 min before intake and 0.5, 1, 1.5, 2 and 4 h thereafter 5 min before intake
Blood samples were centrifuged at approximately 2700g for 10 min, and plasma samples were pipetted into two identically labeled vials for storage at V 208C. Additional samples were drawn to measure endogenous sex steroids and binding proteins as well as to test for pregnancy. Both EE and CMA were determined in plasma with a validated analytical method using derivatization and capillary gas chromatography–mass spectrometry (GC–MS) with negative chemical ionization. CMA was derivatized with pentafluorobenzylhydroxylamine, and EE was derivatized with 3,5-bis-(trifluoromethyl)-benzoylchloride. Internal standards were megestrol acetate for CMA and 2 H4-ethinylestradiol (d4-EE) for EE. Using 1 mL of plasma, limits of quantification were 100 pg/mL for CMA and 10 pg/mL for EE, with calibration ranges of 100–2500 and 10–500 pg/mL, respectively. All measurements were suitably calibrated and subjected to quality control. Pharmacokinetic evaluations were performed on the first 18 of the 22 volunteers eligible for analysis using a noncompartmental method. The area under the (plasma concentration) curve (AUC) was calculated according to the equation of Gibaldi and Perrier [19]: AUC0–t (AUC between t =0 and t) was calculated by the trapezoidal rule, and AUCt–l (AUC between t and infinity) was extrapolated using the terminal half-life of elimination (t 1/2,z ), which was calculated using a log-linear regression analysis [20]. Since concentrations could usually be measured up to 16 h only for EE, AUC0–24 was derived from the extrapolated AUC. The rate of absorption after the first and last administration was characterized by the time (T max) to attain the maximum plasma concentration (C max). Mass balance factor (R 1), accumulation factor (R 2) and theoretical accumulation factor (R theo) were calculated according to the following formulae [21]: R1 ¼ AUCss;md =AUCsd R2 ¼ AUCss;md =AUC024;sd Rtheo ¼ 1=ð1 2e Þ; where ss, sd and md indicate steady state, single dose and multiple doses, respectively, and e = s/t 1/2,z , where s is dosing
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Fig. 1. Mean (n = 18) plasma concentrations of CMA after single and multiple dosing (Day 21 of the treatment cycle) of the oral contraceptive.
Fig. 2. Mean (n = 18) plasma concentrations of EE after single and multiple dosing (Day 21 of the treatment cycle) of the oral contraceptive.
interval (which is 24 h in this case). For CMA, only a small fraction of the dose is represented by the AUC dominated by the terminal half-life. Therefore, R theo was calculated using the beffectiveQ half-life (t 1/2,eff ), defined as t 1/2,eff = ln(2)mean residence time according to Gibaldi and Perrier [22], instead of t 1/2,b . Single- and multiple-dose pharmacokinetic results were compared descriptively.
intervals thereafter: 0–2, 2–4, 4– 6, 6–8, 8–12, 12–24, 24–48, 48–72, 72–96, 96–120, 120–144, 144–168, 168–192, 192–216, 216–240, 240–264 and 264–288 h. Feces were collected as voided into preweighed, labeled containers and analyzed in 24-h periods for up to 288 h. Total radioactivity was determined in urine by liquid scintillation analysis using a Packard TR1600 automatic counter equipped with an automatic standardization system. Feces were combusted in a Packard Tri-Carb 306 Automated Sample Oxidizer prior to scintillation analysis. Cumulative excretion of total radioactivity in urine and feces is presented descriptively as the mean (FSD) of the percentage of administered dose by time interval.
2.2. Conduct and analytical methods of the CMA excretion study After a screening period of up to 14 days, 4 subjects were admitted to the clinic on the evening before dosing. Volunteers fasted from 2300 h on the evening before dosing until 4 h after dosing. Standardized meals were served thereafter. Volunteers were monitored for laboratory parameters and vital signs; adverse events and concomitant medications were recorded. Volunteers received a single oral dose of 2 mg (1.96 MBq) 14 C-CMA dissolved in 1 mL ethanol and dispensed in two separate gelatin capsules. The radiation dose was prepared in compliance with the International Commission of Radiological Protection Guidelines of 1992 [23]. Urine samples were collected in preweighed and labeled containers before taking the study drug and at the following
3. Results 3.1. Single and multiple oral administration of 2 mg CMA and 0.03 mg EE The study was completed by 19 volunteers. Three women dropped out: one because of pregnancy before taking any study medication, one because of weight gain and one because of intracyclic bleeding. The mean age of those who completed the study was 31.6 years, and the mean body weight was 61.0 kg. During
Table 1 Mean (FSD) pharmacokinetic parameters of CMA (Day 21 of the treatment cycle) after single- and multiple-dose administration of the oral contraceptive combination (n = 18) Parameter
Single dose, Cycle 2
Multiple doses, Cycle +1
Multiple doses, Cycle +3
Multiple doses, Cycle +6
AUC (pgd h/mL) AUC0–24/AUCss (pgd h/mL) C max/C ss,max (pg/mL) T max/Tss,max (h) MRT (h) C ss,av (pg/mL) R1 R2 t 1/2,z (h)
14,403F4392 9685F2468 1597.3F458.2 1.61F0.37 24.5F10.7 – – – 25.3F9.8
– 19,361F5505 2213.6F604.0 1.61F0.50 – 807F229 1.41F0.38 2.02F0.40 36.5F8.5
– 15,829F3802 2006.6F508.1 1.47F0.50 – 660F158 1.17F0.34 1.69F0.44 39.1F13.4
– 15,944F3338 2058.6F473.5 1.40F0.42 – 664F139 1.17F0.28 1.70F0.38 38.1F15.1
AUC0–24, AUC between t = 0 and t = 24; C max, peak concentration; C ss,max, peak concentration at steady state; T max, time to maximum concentration; Tss,max, time to maximum concentration at steady state; MRT, mean residence time; C ss,av, average steady-state concentration; R 1, mass balance factor; R 2, accumulation factor; t 1/2,z , terminal half-life of elimination.
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Table 2 Mean (FSD) pharmacokinetic parameters of EE (Day 21 of the treatment cycle) after single- and multiple-dose administration of the oral contraceptive combination (n = 18) Parameter
Single dose, Cycle 2
Multiple doses, Cycle +1
Multiple doses, Cycle +3
Multiple doses, Cycle +6
AUC (pgd h/mL) AUC0–24/AUCss (pgd h/mL) C max/C ss,max (pg/mL) T max/Tss,max (h) MRT (h) C ss,av (pg/mL) R1 R2 t 1/2,z (h)
680F277 600F212 83.6F31.5 1.47F0.36 10.4F4.4 – –
– 1051F563 123.9F36.4 1.92F2.33 – 43.8F23.5 1.69F0.94 1.87F0.98 13.1F5.0
–
– 1006F313 129.8F40.1 1.31F0.39 – 41.9F13.0 1.63F0.58 1.80F0.53 14.2F5.3
7.6F3.7
972F330 130.6F43.0 1.11F0.37 – 40.5F13.8 1.57F0.60 1.73F0.57 12.3F4.7
AUC0–24, AUC between t = 0 and t = 24; C max, peak concentration; C ss,max, peak concentration at steady state; T max, time to maximum concentration; Tss,max, time to maximum concentration at steady state; MRT, mean residence time; C ss,av, average steady-state concentration; R 1, mass balance factor; R 2, accumulation factor; t 1/2,z , terminal half-life of elimination.
the whole study, there were only two missed doses, and all examinations were performed on schedule. No serious or unexpected adverse events were reported. The most common adverse event was headache, mostly rated as mild or moderate. This adverse event was consistently spread over medication-free run-in cycle and medication cycles. Other common adverse events were dysmenorrhea, nausea, breast pain and vaginal discharge. In most cases, the severity was rated as mild to moderate. These adverse events are among those most commonly reported during the intake of combined oral contraceptives. No relevant findings were reported in the other safety assessments. According to the protocol, the first 18 women who completed the study were included in the main pharmacokinetic evaluation. The GC–MS technique was highly accurate for quantifying the plasma concentrations of CMA and EE. The average percentage deviation from the nominal value for the 47 calibration curves of CMA was 3.1% at the lowest level and between 0% and 3.3% at the remaining standard concentrations. Interassay accuracy for CMA measurement ranged from 99.1% to 101.8%, and precision ranged from 5.3% to 8.1%. For EE, the average percentage deviation from the nominal value for the 18 calibration curves was 3.3% at the lowest level and between 0.3% and 4% at the remaining standard concentrations. Interassay accuracy for EE measurement ranged from 97.7% to 103.4%, and precision ranged from 3.9% to 8.6% Figs. 1 and 2 show the mean plasma concentration profiles of CMA and EE, respectively, after single and multiple doses of the oral contraceptive combination (2 mg CMA/0.03 mg EE). Pharmacokinetic parameters calculated for CMA and
EE are presented in Tables 1 and 2, respectively. Trough values for both analytes are listed in Tables 3 and 4. Concentrations of CMA could be measured in most subjects up until 32 h after single dosing and up until 56 h (the last sampling point) after multiple dosing. Concentrations of EE could be measured in most subjects until 16 h after single dosing and up until 24–32 h after multiple dosing. Peak plasma concentrations for CMA and EE were reached within 1 and 2 h after taking the study drug. Mean peak plasma concentrations of CMA were approximately 1600 pg/mL after single-dose administration and rose to approximately 2000 pg/mL after multiple dosing. AUC0–24 for CMA increased from 9685 pgd h/mL after single dosing to an AUCss of 16,000–19,000 pgd h/mL after multiple dosing; for EE, it increased from 600 pgd h/mL after single dosing to about 1000 pgd h/mL after multiple dosing. For both CMA and EE, AUCss and C ss,max remained constant throughout the entire six cycles. Accordingly, average trough values of about 400–500 pg/mL for CMA and 20–40 pg/mL for EE were reached at the latest on Day 15 and remained constant throughout the entire study period. For CMA, a mean t 1/2,z of 25 h after single dose and mean t 1/2,z of 36–39 h after multiple doses were determined. For EE, a mean t 1/2,z of 7.6 h after single dose and mean t 1/2,z of 12–14 h after multiple doses were found. R 1 values of 1.2–1.4 for CMA and 1.6–1.7 for EE were calculated. Corresponding R 2 values of 1.7–2 for CMA and 1.7–1.9 for EE were determined.
Table 3 Mean (FSD) trough values for CMA after multiple daily administration of a combination of 2 mg CMA and 0.03 mg EE
Table 4 Mean (FSD) trough values for EE after multiple daily administration of a combination of 2 mg CMA and 0.03 mg EE
Day
Cycle +1 (pg/mL)
Cycle +3 (pg/mL)
Cycle +6 (pg/mL)
Day
Cycle +1 (pg/mL)
Cycle +3 (pg/mL)
Cycle +6 (pg/mL)
10 15 17 19 21
446F103 497F144 513F173 507F197 494F150
– 402F120 402F143 386F123 393F140
– 390F164 381F157 385F116 412F130
10 15 17 19 21
16F4 27F26 30F27 24F22 19F6
– 39F40 43F44 39F45 20F6
– 25F12 21F7 20F8 20F6
3.2. Single-dose study of renal and fecal excretion of CMA The four subjects included in the excretion study were aged between 31 and 40 years and weighed between 47.0 and 74.1 kg.
R. Terlinden et al. / Contraception 74 (2006) 239 – 244 Table 5 Mean (FSD) cumulative excretion of total radioactivity in urine and feces as a percentage of dose (n = 4) Time (h)
Urine
Feces
Total recovery
2 4 6 8 12 24 72 120 144 240 288
0.5F0.4 3.1F1.1 5.3F0.9 6.4F1.4 8.8F1.8 13.4F2.1 30.7F4.2 38.9F4.1 41.4F3.7 45.2F3.8 47.4a
– – – – – – 15.5F15.6 31.6F13.5 35.9F10.9 42.1F8.5 37.4a
0.5F0.4 3.1F1.1 5.3F0.9 6.4F1.4 8.8F1.8 13.4F2.1 46.2F16.7 70.5F14.3 77.3F10.9 87.3F6.4 84.8a
a
n = 2.
Table 5 summarizes renal and fecal excretion of total radioactivity. Two hundred forty hours post dose, the mean dose recovered was 87.3F6.4% (range, 81.0–93.3%). Urinary excretion accounted for 45.2% (range, 40.7– 48.5%) of the dose, and excretion in feces accounted for 42.1% (range, 32.4–52.6%). 4. Discussion In the present study, t 1/2,z of CMA after a single dose was approximately 25 h, and it was approximately 36–39 h during multiple dosing. Because of the higher plasma concentrations of CMA during multiple dosing, CMA was quantifiable up to approximately 56 h, as compared with 38 h after single dosing. Thus, more data points could be used for calculating the terminal regression line, and the value may be more accurate. The single-dose t 1/2,z of CMA in the present study is shorter than the value reported by Chassard et al. [18], although t 1/2,z during multiple dosing is similar. However, the dose in the cited study was five times greater than that in the present study, and hence, CMA concentrations could be quantified for a longer period after dosing, allowing for a more accurate determination of t 1/2,z . The plasma concentrations of CMA were quantified using the same GC–MS method as in the present multiple-dose study. In theory, 90–99% of steady-state concentrations are reached after 3.3–7 half-lives [21]; hence, it would be expected that steady state was reached on average after 5–11 days. Since trough concentrations were not measured before Day 15 (Day 10 for Cycle +1), the present study confirms that steady state is reached at the latest at Day 15, possibly even earlier. Accumulation, as measured by the accumulation factor R 2, was approximately twofold for Cycle +1 with respect to single dose and 1.7 for Cycles +3 and +6. This compares reasonably well with theoretical accumulation factors of 2–2.2. The R 1 values of 1.4 in Cycle +1 and 1.2 in Cycles +3 and +6 suggest that the pharmacokinetics of CMA is linear at this dose and, therefore, that resorption is constant.
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AUCss, C max and trough values remained constant over the entire study period of 6 months, demonstrating stable, timeindependent pharmacokinetics. In the excretion balance study, the amount excreted by renal and fecal routes was roughly equal. This, together with the relatively long half-life of CMA, is in agreement with enterohepatic recirculation of CMA or its metabolites. Although CMA has been used in oral contraceptives for decades, only two studies of its pharmacokinetic profile have been published in the scientific literature. In the seminal study of the pharmacokinetics of CMA dating from the 1970s [17], radiolabeled CMA was administered as a single intravenous dose. The dose of CMA, however, was not explicitly stated; only the dose of radioactivity was reported (60–90 ACi). The subjects, aged between 34 and 52 years, were hospital patients awaiting a total hysterectomy and were not representative of women who would normally take oral contraceptives. The analytical methods consisted of several extraction steps, followed by thin-layer chromatography and liquid scintillation counting. The validity of these methods, although unknown, seems questionable based on current knowledge. Mean t 1/2,z was 80.1 h for total radioactivity (calculated for five subjects) and 81.8 h for CMA-specific radioactivity (calculated for four subjects). In addition to the unknown validity and presumed low sensitivity and low accuracy of the bioanalytical methods used in the 1970s and the nonrepresentative study population, the small number of subjects and the limited number of data points used to calculate the pharmacokinetic parameters (for t 1/2,z , 4 or 5 points were used) further detract from the reliability of the results. Nevertheless, the long t 1/2,z of over 80 h is still quoted in the literature [24,25]. Chassard et al. [18] investigated the relative bioavailability of two oral doses of CMA (25 mg and 10 mg) after single dosing in 12 healthy women between 18 and 30 years old. The pharmacokinetic parameters were similar for the two formulations, with t 1/2,z at approximately 36 h and T max at 2.5 h. The pharmacokinetics of EE in the present study agreed well with results published in the literature. During multiple dosing, t 1/2,z was around 13 h, which lies within the wide range of 6 to 27 h reported for t 1/2,z of EE [26,27]. In modern oral contraceptives, the dose of EE is low (0.03 mg), making accurate determination of pharmacokinetic parameters difficult. In our study, the lower limit of quantification (10 pg/mL) was reached between 8 and 16 h after administration of a single dose — too soon for an accurate determination of t 1/2,z , accumulation factor or mass balance factor. During multiple dosing, plasma concentrations of EE could be quantified for a longer period, which may explain why the measured t 1/2,z was longer. R 1 and R 2 values for EE were higher than theoretically predicted (R 2 = 1.7–1.9; R theo = 1.2–1.4) but well within the wide range reported in literature [11,28–31]. The overestimation of R 1 and R 2 is not surprising given that, on average, 25% of the AUC and 17% of the AUC0–24 were extrapolated.
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