Pharmacokinetic Properties of a New Controlled-Release Formulation of Carvedilol

Pharmacokinetic Properties of a New Controlled-Release Formulation of Carvedilol David M. Tenero, PharmD,a,* Linda S. Henderson, PhD,b Charlotte A. Baidoo, MMath,c Angela H. Harter, MS,d Andrea M. Campanile, MS,d Theodore M. Danoff, MD, PhD,b and Duane Boyle, PharmDa This review summarizes the pharmacokinetics (PK) of carvedilol after administration of a new once-daily controlled-release (CR) formulation. The plasma concentrationtime profiles for both R(ⴙ)- and S(ⴚ)-carvedilol indicate that carvedilol CR will provide coverage over a 24-hour period similar to the current immediate-release (IR) twice-daily formulation. Exposures for both enantiomers, based on area under the curve (AUC), maximum plasma concentrations (Cmax), and trough concentrations, are equivalent for carvedilol CR compared with carvedilol IR. Cmax and AUC of the enantiomers of carvedilol increase in an approximate dose-proportional manner after administration of carvedilol CR over the dose range of 10 – 80 mg, indicating that the formulation provides consistent PK performance across the dose strengths proposed for marketing. The intrasubject and intersubject variability of carvedilol CR was comparable to carvedilol IR. For carvedilol CR, mean AUC and Cmax were increased <20% after a high-fat meal compared with a standard meal. The CR and IR formulations of carvedilol exhibited equivalent steady-state PK characteristics in the target hypertension and heart failure populations. The availability of once-daily dosing is expected to improve treatment adherence and thereby enhance the effectiveness of carvedilol in routine clinical use. © 2006 Elsevier Inc. All rights reserved. (Am J Cardiol 2006;98[suppl]:5L-16L)

Carvedilol is currently marketed as an immediate-release (IR) tablet formulation to treat essential hypertension and mild-to-severe congestive heart failure and to reduce cardiovascular mortality in clinically stable patients with post– myocardial infarction (MI) left ventricular dysfunction (LVD) with or without symptomatic heart failure. Carvedilol IR is taken twice daily for all 3 indications. The clinical pharmacology and safety profiles of the IR formulation of carvedilol have been established in previous studies.1 Carvedilol was recently formulated as a controlledrelease (CR) drug product suitable for once-daily administration. This review summarizes studies in which the pharmacokinetics (PK) of carvedilol were determined after administration of the CR formulation and include assessment of relative bioavailability, dose proportionality, food effect, diurnal variation, and multiple-dose PK in patients with hypertension and heart failure, and the effect of gastric pH. In these studies, carvedilol CR was typically administered under fed conditions (usually after a standard

a Department of Clinical Pharmacokinetics, Modeling, and Simulation; Department of Clinical Pharmacology and Discovery Medicine; cDepartment of Clinical Pharmacology Statistics and Programming; and dDepartment of Clinical Sciences and Study Operations, GlaxoSmithKline, King of Prussia, Pennsylvania, USA. *Address for reprints: David M. Tenero, PharmD, GlaxoSmithKline, 709 Swedeland Road, UW2109, King of Prussia, Pennsylvania 19406. E-mail address: [email protected]. b

0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2006.07.014

moderate-calorie breakfast), as recommended for carvedilol IR,1 and the plasma concentrations of carvedilol and/or its enantiomers R(⫹)- and S(⫺)-carvedilol were determined. Nonselective ␤-adrenoreceptor– blocking activity is present in the S(⫺) enantiomer, and ␣-adrenergic blocking activity is present in both R(⫹) and S(⫺) enantiomers at equal potency.1,2

Formulation The new carvedilol CR capsule formulation contains 3 carvedilol phosphate (anhydrate) microparticle components in the following proportions: 12.5% IR, 37.5% Micropump IIa, and 50% Micropump IIc (Flamel Technologies, SA, Venissieux, France). Each Micropump component is coated with a pH-sensitive polymer (pH 5.5 for Micropump IIa and pH 6.4 – 6.8 for Micropump IIc), with release related to the pH-dependent solubility of the polymer. The dose strengths (3.125, 6.25, 12.5, and 25 mg administered twice daily) of the marketed carvedilol IR tablet formulation are based on carvedilol free base. As shown in Table 1, the proposed dose strengths (10, 20, 40, and 80 mg administered once daily) of the CR capsule formulation are larger, are based on the use of carvedilol phosphate (higher molecular weight than carvedilol free base), and contain a greater amount of carvedilol free base compared with the IR formulation (approximately 30% higher to compensate for lower bioavailwww.AJConline.org

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The American Journal of Cardiology (www.AJConline.org) Vol 98 (7A) October 2, 2006 Table 1 Dose conversion chart for carvedilol IR and carvedilol CR Carvedilol CR (Carvedilol Phosphate)

Marketed Carvedilol Formulation (IR)*: Total Daily Dose of Carvedilol Free Base

Carvedilol Free Base Equivalent

Labeled Dose†

6.25 mg 12.5 mg 25 mg 50 mg

8.1 mg 16.2 mg 32.4 mg 64.8 mg

10 mg 20 mg 40 mg 80 mg

CR ⫽ controlled release; IR ⫽ immediate release. *Administered twice daily. † The larger numbers for the doses of carvedilol CR are based on the use of carvedilol phosphate (higher molecular weight than carvedilol free base) and a greater amount of carvedilol free base compared with the IR formulation. The relative bioavailability area under the curve [AUC], maximum plasma concentration [Cmax], and trough drug concentration [C␶]) of carvedilol is equivalent after administration of the final CR formulation once daily and the IR formulation twice daily.

ability). Importantly, the relative bioavailability (area under the curve [AUC], maximum plasma concentrations [Cmax], and trough drug concentration [C␶]) of carvedilol is equivalent after administration of the CR formulation once daily and the IR formulation twice daily.

Relative Bioavailability The goal in the development of a once-daily CR formulation of carvedilol was to achieve similar exposure compared with that observed for IR carvedilol administered twice daily. The single-dose PK of the CR formulation of carvedilol has been characterized and compared with the IR formulation (25 mg every 12 hours for 2 doses) in young, healthy volunteers. In this study, the CR formulation that was evaluated contained the same microparticle types and ratio as the proposed commercial product; however, the formulation differed from the proposed commercial product in that the amount of drug substance was slightly less than the amount at the top dose of the proposed commercial product (60 mg carvedilol free base vs 64.8 mg free base [80 mg carvedilol phosphate]). The mean concentration-time profiles for the enantiomers of carvedilol are shown in Figures 1 and 2. The prolongedrelease characteristics of the CR formulation were evident because median time to maximum observed plasma concentration (tmax) was approximately 3.5 hours longer for both R(⫹)- and S(⫺)-carvedilol after administration of the carvedilol CR capsule compared with the IR tablet (approximately 5 and 1.5 hours, respectively). The mean retard quotient (a measure of prolonged release and determined as the width of the plasma concentration-time profile at a plasma concentration equal to one half of the Cmax for the CR formulation relative to the corresponding width for the IR formulation) value of approximately 2 for both enantiomers suggested medium retardation for the CR formulation.3 The relative bioavailability of the

CR formulation was similar to that observed for the IR formulation. The AUC from zero (before dosing) to the time of last quantifiable concentration (AUC[0 –t]) for R(⫹)- and S(⫺)-carvedilol was increased approximately 10% and 19%, respectively, after administration of the CR formulation compared with the carvedilol IR tablet, whereas the Cmax for R(⫹)- and S(⫺)-carvedilol was increased approximately 9% after administration of the CR formulation.

Dose Proportionality It is important to show that a CR formulation provides consistent PK performance across the proposed dose strengths. The dose proportionality of R(⫹)- and S(⫺)carvedilol was investigated after single-dose administration of 10, 20, 40, and 80 mg carvedilol CR to 39 young, healthy volunteers. Exposure for both enantiomers was shown to increase with increasing dose (Figures 3 and 4). The geometric mean (range) terminal elimination halflife was similar for R(⫹)- and S(⫺)-carvedilol at 10.4 hours (4.1–28.7 hours) and 11.5 hours (4.9 –29.2 hours), respectively. This does not include data for the CR 10-mg dose level because concentration-time profiles for both enantiomers were not consistently well described. Because of stereoselective first-pass metabolism, plasma levels of R(⫹)-carvedilol are typically higher compared with those observed for S(⫺)-carvedilol.4 On average, the R-to-S ratio for carvedilol CR was 2.42–2.57 for the AUC and 2.44 –2.64 for the Cmax across the 4 doses. These results are consistent with previous results observed for the IR formulation in healthy volunteers4 and in patients with congestive heart failure,5 suggesting the stereoselectivity of carvedilol is not dependent on the rate of absorption. Dose proportionality was assessed by the power model (linear regression model relating the log of AUC or Cmax to

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Figure 1. Mean R(⫹)-carvedilol concentration-time profiles: carvedilol immediate release (IR) and controlled release (CR). Pilot CR formulation (60 mg carvedilol free base) was used in this study. The top CR dose strength proposed for marketing is 80 mg carvedilol phosphate (64.4 mg carvedilol free base). pfb ⫽ pure free base.

Figure 2. Mean S(⫺)-carvedilol concentration-time profiles: carvedilol immediate release (IR) and controlled release (CR). Pilot CR formulation (60 mg carvedilol free base) was used in this study. The top CR dose strength proposed for marketing is 80 mg carvedilol phosphate (64.4 mg carvedilol free base). pfb ⫽ pure free base.

the log of the dose) and the analysis of variance. Based on both the power model analysis (Table 2) and the analysis of variance (results not shown), there were approximate dose-proportional increases in Cmax and AUC of R(⫹)and S(⫺)-carvedilol with increasing (10 – 80 mg) single oral doses of the carvedilol CR formulation. These results demonstrate that the CR formulation provides consistent PK performance across the dose strengths proposed for marketing.

Effect of Food on Oral Absorption The effect of food on the rate and extent of absorption of carvedilol after administration of carvedilol CR has been evaluated to rule out the occurrence of any “dose dumping,” the unintended rapid release of all or a significant fraction of drug, from the CR formulation. The label for the IR formulation of carvedilol recommends that it “should be taken with food to slow the rate of absorption and reduce the

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Figure 3. Mean R(⫹)-carvedilol concentration-time profiles: carvedilol controlled release (CR) at varying doses.

Figure 4. Mean S(⫺)-carvedilol concentration-time profiles: carvedilol controlled release (CR) at varying doses.

incidence of orthostatic effects.”1 In accordance with the label for carvedilol IR, patients in the phase 3 studies conducted with the CR formulation of carvedilol were instructed to take carvedilol with food. Most clinical pharmacology studies conducted to support the development of carvedilol CR also administered the CR and IR formulations after subjects received a standard meal (a standard meal of moderate calories and low-to-moderate fat). Steady-state carvedilol exposure (AUC, Cmax, and predose C␶) has been shown to be similar after administration of the CR and IR formulations after a standard meal.6,7 Thus, administration of carvedilol with food (the standard meal) is considered the

“reference” treatment when evaluating the effect of food on carvedilol CR. The effect of food on the CR formulation of carvedilol was determined after administration of single oral doses of the highest strength (80 mg) of the proposed commercial CR formulation to young, healthy volunteers. Carvedilol CR was administered after a standard meal (n ⫽ 19) and after a high-fat meal (n ⫽ 20), as well as in the fasted state (n ⫽ 19) and when sprinkled on applesauce after a standard meal (n ⫽ 20). Administration of the CR carvedilol capsule with a high-fat meal resulted in a small (⬍20%) increase in AUC and Cmax compared with administration of the CR

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Table 2 Point estimates and 90% confidence intervals (CIs) for slopes Carvedilol Enantiomer

Parameter

Effect

Point Estimate*

90% CI

R(⫹)-carvedilol

AUC(0–t=) Cmax AUC(0–t=) Cmax

Log(dose) Log(dose) Log(dose) Log(dose)

1.06 1.06 1.08 1.09

1.03–1.09 1.02–1.11 1.05–1.11 1.05–1.14

S(⫺)-carvedilol

AUC(0 –t=) ⫽ area under the concentration-time curve from zero (before dosing) to time of last quantifiable concentration within a subject across all treatments. *A slope of approximately 1 implies dose proportionality.

capsule with a standard meal (Table 3). There was no evidence of dose dumping after administration of the CR formulation with a high-fat meal. Geometric mean Cmax was 83 ng/mL (range, 36.1–205 ng/mL) when the CR formulation (65 mg pure free base) was dosed after a high-fat meal, whereas geometric mean Cmax after administration of a comparable single dose of the IR formulation (50 mg) was approximately 150 ng/mL (range, 50.4 –366 ng/mL).8 When the CR formulation was administered in the fasted state compared with administration after a standard meal, AUC and Cmax were decreased, on average, by 27% and 43%, respectively (Table 4). The lower exposure after administration of carvedilol CR in the fasted state is likely related to poorer absorption of carvedilol in the lower gastrointestinal tract. In the fasted state, the transit time for the CR formulation is faster, resulting in less residence time in the small intestine and therefore less carvedilol absorption. Sprinkling the contents of the carvedilol CR capsule on applesauce after a standard meal did not appear to have a significant effect on overall exposure compared with administration of the intact capsule after a standard meal alone (Table 5). This alternative method of dosing may be useful in patients who have difficulty swallowing.

Diurnal Variation The IR formulation of carvedilol is dosed twice daily. Administration of the evening dose showed a carvedilol concentration-time profile with a lower Cmax and a delay in tmax compared with morning administration. The effect of evening dosing (fed state) on the single-dose PK of the enantiomers of carvedilol relative to morning dosing (fed state) when administered as the CR formulation (80 mg) was evaluated in 22 young, healthy volunteers. The extent of absorption of R(⫹)- and S(⫺)-carvedilol (based on AUC) was decreased ⬍10% after evening administration compared with morning administration, and the 90% confidence intervals (CIs) were within the accepted limits (0.80 –1.25) for bioequivalence criteria (Table 6). Cmax was decreased to a greater extent with evening dosing [approximately 15% for R(⫹)-carvedilol and 20% for S(⫺)carvedilol] because of a decrease in the rate of absorption with evening dosing (tmax delayed approximately 1.5 hours). A

circadian dependency has been reported for the PK of a number of drugs and may provide an explanation for the change in PK of carvedilol with evening administration.9 –11 However, the PK differences between morning and evening administration of carvedilol CR are modest. Intrasubject and Intersubject Variability It is important to assess the variability of a CR formulation, both within a subject and between subjects, and to compare it with the variability observed for the IR formulation. To assess the intrasubject variability of carvedilol after administration of carvedilol CR, 20 young, healthy subjects received single oral doses of the CR formulation in the morning on 2 separate occasions. Intrasubject variability estimates after replicate administration of the CR formulation were compared with estimates for the IR formulation, which were obtained from a bioequivalence study in which a single dose of carvedilol 50 mg (2 ⫻ 25 mg) and a proposed commercial 50-mg carvedilol tablet were found to be bioequivalent (n ⫽ 44).8 The intrasubject variability estimates for AUC and Cmax were comparable for the carvedilol CR and IR formulations and were ⬍30% for both parameters (Table 7). Intersubject variability estimates for AUC and Cmax were obtained in 2 studies in which the final CR formulation and the IR formulation were administered. In the first study, patients with hypertension (n ⫽ 47) received carvedilol (6.25 mg twice daily or 25 mg twice daily) or the equivalent dose of carvedilol CR (20 or 80 mg) in a randomized, crossover, repeat-dose design.6 In the other study, patients with mild-to-severe heart failure and patients with post-MI LVD (n ⫽ 42) received carvedilol (3.125, 6.25, 12.5, or 25 mg twice daily) and then the equivalent dose of carvedilol CR (10, 20, 40, or 80 mg) in a nonrandomized, crossover, repeat-dose design.7 The intersubject variability estimates for AUC and Cmax were comparable for the CR and IR formulations (Table 8). Multiple-Dose Pharmacokinetics in Patients with Hypertension The multiple-dose PK of the final CR formulation of carvedilol has been characterized in 78 patients with hypertension. Pa-

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The American Journal of Cardiology (www.AJConline.org) Vol 98 (7A) October 2, 2006 Table 3 Comparison of high-fat meal versus standard meal Parameter †

AUC(0–t) Cmax† tmax (hr)‡

Regimen Comparison*

Point Estimate

90% CI

C:B C:B C–B

1.18 1.19 0.00

1.04–1.35 1.02–1.39 ⫺0.50–0.50

AUC(0 –t) ⫽ area under the concentration-time curve from zero (before dosing) to time of last quantifiable concentration; Cmax ⫽ maximum plasma concentration; CR ⫽ controlled release; tmax ⫽ time to maximum observed plasma concentration. *Regimen B ⫽ 80 mg carvedilol CR after standard meal; regimen C ⫽ 80 mg carvedilol CR after a high-fat meal. † Point estimate represents the ratio of adjusted geometric means between regimens. ‡ Point estimate represents the estimated median difference between regimens.

Table 4 Comparison of fasting state versus standard meal Parameter †

AUC(0–t) Cmax† tmax (hr)‡

Regimen Comparison*

Point Estimate

90% CI

A:B A:B A–B

0.73 0.57 ⫺1.00

0.64–0.83 0.49–0.67 ⫺2.00–0.00

AUC(0 –t) ⫽ area under the concentration-time curve from zero (before dosing) to time of last quantifiable concentration; Cmax ⫽ maximum plasma concentration; CR ⫽ controlled release; tmax ⫽ time to maximum observed plasma concentration. *Regimen A ⫽ 80 mg carvedilol CR under fasting conditions; regimen B ⫽ 80 mg carvedilol CR after standard meal. † Point estimate represents the ratio of adjusted geometric means between regimens. ‡ Point estimate represents the estimated median difference between regimens.

Table 5 Comparison of applesauce sprinkled with capsule contents after standard meal versus intact capsule after standard meal Parameter

Regimen Comparison*

Point Estimate

90% CI

AUC(0–t)† Cmax† tmax (h)‡

D:B D:B D–B

0.99 0.82 0.00

0.87–1.12 0.70–0.96 ⫺0.50–1.00

AUC(0 –t) ⫽ area under the concentration-time curve from zero (before dosing) to time of last quantifiable concentration; Cmax ⫽ maximum plasma concentration; CR ⫽ controlled release; tmax ⫽ time to maximum observed plasma concentration. *Regimen B ⫽ 80 mg carvedilol CR after a standard meal; regimen D ⫽ 80 mg carvedilol CR sprinkled on applesauce after a standard meal. † Point estimate represents the ratio of adjusted geometric means between regimens. ‡ Point estimate represents the estimated median difference between regimens.

tients with hypertension received carvedilol IR (6.25 or 25 mg twice daily) or the equivalent dose of carvedilol CR (20 or 80 mg once daily) for ⱖ7 days in a randomized, crossover design.6 The comparative mean steady-state concentration-time profiles for R(⫹)- and S(⫺)-carvedilol after once-daily administration of carvedilol CR (80 mg) and twice-daily administration of carvedilol IR tablets (25 mg twice daily) are provided in Figures 5 and 6. As observed after single dosing, the prolonged-release characteristics of the CR formulation were evident because median tmax was approximately 3.5 hours longer

for both enantiomers after administration of the carvedilol CR capsules compared with the IR tablets. On average, the fluctuation index (the CR–IR ratio for [Cmax ⫺ Cmin]/Css where Cmin is the minimum plasma concentration and Css is the steady-state concentration) for both R(⫹)- and S(⫺)-carvedilol was approximately 1, indicating that the peak-to-trough fluctuation in plasma concentration for carvedilol after administration of the CR formulation once daily was similar to that of the IR formulation after twice-daily administration.12 At both dose levels, the PK parameters for R(⫹)- and

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Table 6 Point estimates and 90% confidence intervals (CIs) for comparison of evening to morning dosing Carvedilol Enantiomer

Parameter

Regimen Comparison*

Point Estimate†

90% CI

R(⫹)-carvedilol

AUC(0–t) Cmax tmax‡ (hr) AUC(0–t) Cmax tmax‡ (hr)

B:A B:A B–A B:A B:A B–A

0.92 0.85 1.50 0.91 0.81 1.50

0.81–1.04 0.72–1.00 1.00–2.50 0.80–1.03 0.69–0.96 0.56–2.50

S(⫺)-carvedilol

AUC(0 –t) ⫽ area under the concentration-time curve from zero (before dosing) to time of last quantifiable concentration; Cmax ⫽ maximum plasma concentration; CR ⫽ controlled release; tmax ⫽ time to maximum observed drug concentration. *Regimen A ⫽ 80 mg carvedilol phosphate CR dosed in morning under fed conditions; regimen B ⫽ 80 mg carvedilol phosphate CR dosed in evening under fed conditions. † Point estimate represents the ratio of adjusted geometric means between regimens. ‡ Point estimate represents the estimated median difference between regimens.

Table 7 Intrasubject variability of carvedilol CR and carvedilol IR Carvedilol Enantiomer R(⫹)-carvedilol S(⫺)-carvedilol

Parameter

Carvedilol CR*

Carvedilol IR†

AUC(0–t) (ng · hr/mL) Cmax (ng/mL) AUC(0–t) (ng · hr/mL) Cmax (ng/mL)

14.7% 26.0% 15.9% 29.9%

16.5% 24.3% 22.4% 29.7%

AUC(0 –t) ⫽ area under the concentration-time curve from zero (before dosing) to time of last quantifiable concentration; Cmax ⫽ maximum plasma concentration; CR ⫽ controlled release; IR ⫽ immediate release. *Single dose of 80 mg carvedilol CR on 2 separate occasions. † Two of the 25 mg tablets were given at the same time for a total dose of 50 mg.

Table 8 Intersubject variability of carvedilol CR and carvedilol IR Study 2†

Study 1* Carvedilol Enantiomer

Parameter

CR

IR

CR

IR

R(⫹)-carvedilol

AUC(0–24) (ng · hr/mL) Cmax (ng/mL) C␶ (ng/mL) AUC(0–24) (ng · hr/mL) Cmax (ng/mL) C␶ (ng/mL)

67% 66% 100% 54% 56% 85%

61% 54% 92% 50% 54% 62%

104% 85% 169% 80% 71% 119%

94% 70% 144% 71% 61% 98%

S(⫺)-carvedilol

AUC ⫽ area under the concentration-time curve from zero (before dosing) to 24 hr postdose; Cmax ⫽ maximum plasma concentration; C␶ ⫽ trough drug concentration; CR ⫽ controlled release; IR ⫽ immediate release. *Steady-state dosing of 80 mg carvedilol CR and 25 mg carvedilol IR twice daily in patients with hypertension. † Steady-state dosing of 80 mg carvedilol CR and 25 mg carvedilol IR twice daily in patients with heart failure.

S(⫺)-carvedilol were similar for the 2 formulations. Based on a pooled analysis, bioequivalence was achieved for the CR and IR formulations of carvedilol because point estimates and corresponding 90% CIs for AUC, Cmax, and C␶ were within bioequivalence limits of 80%–125% (Table 9). Thus, the steady-state performance of carvedilol CR is equivalent to that of the IR formulation. Steady-state exposure to the 4=-hydroxyphenyl (M4) metabolite of carvedilol after administration of the CR and IR formulations was determined at the high-dose level (CR 80 mg

once daily and IR 25 mg twice daily). After administration of each formulation, M4 metabolite concentrations decreased in parallel with carvedilol concentrations, suggesting that M4 metabolite elimination is formation-rate limited (Figure 7). On average, AUC(0 –t) and Cmax values for M4 were similar for carvedilol IR and carvedilol CR. Additionally, the mean M4-to-carvedilol ratio for AUC(0 –t) and Cmax was similar for the 2 formulations (approximately 9%– 10%). These data for M4 are consistent with results previously observed in healthy volunteers and in patients

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Figure 5. Mean steady-state concentration-time profiles for R(⫹)-carvedilol. CR ⫽ controlled release; IR ⫽ immediate release.

Figure 6. Mean steady-state concentration-time profiles for S(⫺)-carvedilol. CR ⫽ controlled release; IR ⫽ immediate release.

with heart failure after administration of the IR formulation.5 Preclinical studies in conscious rabbits have demonstrated that the M4 metabolite possesses ␤-adrenoceptor– blocking activity (approximately 13 times more potent compared with carvedilol) but does not possess

significant vasodilating activity.1 Despite markedly lower plasma concentrations for metabolite M4 compared with carvedilol, it is possible that this metabolite could contribute to the ␤-blocking activity of carvedilol because of its higher potency.

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Table 9 Results of the pooled analysis for comparisons of carvedilol CR and carvedilol IR Carvedilol Enantiomer

Parameter

Comparison of Interest

Point Estimate*

90% CI

R(⫹)-carvedilol

AUC(0–t) Cmax C␶ AUC(0–t) Cmax C␶

CR:IR CR:IR CR:IR CR:IR CR:IR CR:IR

1.06 0.94 0.89 1.15 0.98 0.99

1.02–1.10 0.86–1.03 0.81–0.99 1.10–1.20 0.89–1.09 0.91–1.08

S(⫺)-carvedilol

AUC(0 –t) ⫽ area under the concentration-time curve from zero (before dosing) to time of last quantifiable concentration; Cmax ⫽ maximum plasma concentration; C␶ ⫽ trough drug concentration; CR ⫽ controlled release; IR ⫽ immediate release. *Point estimate represents the ratio of adjusted geometric means between regimens.

Figure 7. Mean steady-state concentration-time profiles of carvedilol and 4=-hydroxyphenyl carvedilol (M4) after administration of carvedilol immediate release (IR) 25 mg every 12 hours and carvedilol controlled release (CR) 80 mg every 24 hours.

Population Pharmacokinetics in Patients with Hypertension The population PK of R(⫹)- and S(⫺)-carvedilol were characterized in 303 patients with essential hypertension after once-daily administration of 20, 40, and 80 mg carvedilol CR.13 The final population model showed that the oral clearance of R(⫹)-carvedilol was approximately 45% lower in poor metabolizers of cytochrome P450 (CYP)2D6 compared with extensive metabolizers. The oral clearance of S(⫺)-carvedilol was not affected by genotype status. These results are consistent with those reported previously in healthy volunteers where poor metabolizers of debrisoquin (a substrate for CYP2D6) were shown to have significantly lower oral clearance of R(⫹)-carvedilol, but not S(⫺)-carvedilol, compared with extensive metabolizers.14 The final population model did show that the oral clearance of S(⫺)-carvedilol was

slightly lower (approximately 15%) in women compared with in men; however, this small effect is not considered to be clinically relevant.

Multiple-Dose Pharmacokinetics in Patients with Heart Failure and Patients with Post–Myocardial Infarction and with Left Ventricular Dysfunction The multiple-dose PK of the CR formulation of carvedilol was characterized in 173 patients with mild-tosevere heart failure or asymptomatic post-MI LVD.7 These patients received carvedilol IR (3.125, 6.25, 12.5, or 25 mg twice daily) and then the equivalent dose of carvedilol CR (10, 20, 40, or 80 mg once daily) for 14 days in a nonrandomized, crossover design. The comparative mean steady-state concentration-time profiles for R(⫹)- and S(⫺)-carvedilol after once-daily administra-

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Figure 8. Mean steady-state concentration-time profiles for R(⫹)-carvedilol after administration of carvedilol immediate release (IR) and carvedilol controlled release (CR).

Figure 9. Mean steady-state concentration-time profiles for S(⫺)-carvedilol after administration of carvedilol immediate release (IR) and carvedilol controlled release (CR).

tion of carvedilol CR (80 mg) and twice-daily administration of carvedilol IR (25 mg) are provided in Figures 8 and 9. As observed after single dosing, the prolongedrelease characteristics of the CR formulation were evident because median tmax was approximately 3 hours longer for both enantiomers after administration of the carvedilol CR capsules compared with the IR tablets. On average, the fluctuation index for both R(⫹)- and S(⫺)carvedilol was approximately 1, indicating that the peakto-trough fluctuation in plasma concentration for carvedilol after administration of the CR formulation once daily was similar to that of the IR formulation after twice-daily administration.12 At all dose levels, the PK parameters for R(⫹)- and S(⫺)-carvedilol were similar for the 2 formulations. Based on a pooled analysis, bioequivalence was achieved for the CR and IR formulations of carvedilol because point estimates and corresponding 90% CIs for AUC, Cmax, and C␶

were within bioequivalence limits of 80%–125% (Table 10). Thus, the steady-state performance of carvedilol CR is equivalent to that of the IR formulation.

Effect of pH on the Controlled-Release Formulation of Carvedilol The CR formulation of carvedilol contains enteric-coated microparticles that are intended to delay the release of carvedilol until the capsule passes through the acidic environment of the stomach. With increased gastric pH, the enteric coating may disintegrate sooner, thus potentially altering the absorption of carvedilol from the CR formulation. The effect of repeat oral doses of a proton pump inhibitor (pantoprazole 40 mg once daily for 7 days) on a single oral dose of a 2-component pilot CR capsule formulation (25 mg) of carvedilol in 23 healthy

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Table 10 Results of the pooled analysis for comparisons of carvedilol CR and carvedilol IR Carvedilol Enantiomer

Parameter

Comparison of Interest

Point Estimate*

90% CI

R(⫹)-carvedilol

AUC(0–24) Cmax C␶ AUC(0–24) Cmax C␶

CR:IR CR:IR CR:IR CR:IR CR:IR CR:IR

1.06 0.95 0.92 1.16 1.00 1.03

1.01–1.12 0.89–1.02 0.85–1.01 1.10–1.22 0.94–1.08 0.95–1.12

S(⫺)-carvedilol

AUC(0 –24) ⫽ area under the concentration-time curve from zero (before dosing) to 24 hr postdose; Cmax ⫽ maximum plasma concentration; C␶ ⫽ trough drug concentration; CR ⫽ controlled release; IR ⫽ immediate release. *Point estimate represents the ratio of adjusted geometric means between regimens.

Table 11 Comparison of carvedilol CR alone and with concomitant pantoprazole administration Parameter †

AUC(0–t) Cmax† tmax (hr)‡

Regimen Comparison*

Point Estimate

90% CI

B:A B:A B–A

1.03 1.10 0.00

0.98–1.10 0.98–1.24 ⫺0.50–0.50

AUC(0 –t=) ⫽ area under the concentration-time curve from zero (before dosing) to last time of quantifiable concentration within a subject across all treatments; Cmax ⫽ maximum plasma concentration; CR ⫽ controlled release; tmax ⫽ time to maximum observed plasma-concentration. *Regimen A ⫽ 25 mg carvedilol CR alone; regimen B ⫽ 40 mg pantoprazole for 7 days plus 25 mg carvedilol CR on day 7. † Point estimates represents the ratio of adjusted geometric means between regimens. ‡ Point estimate represents the estimated median difference between regimens.

adult subjects was evaluated. Compared with carvedilol CR alone, subjects receiving pantoprazole plus carvedilol CR had AUC values approximately 3%– 4% higher on average, whereas Cmax was approximately 10% higher on average (Table 11). Median tmax was identical for both treatment regimens. The corresponding 90% CIs for the ratios of AUC and Cmax for pantoprazole plus carvedilolto-CR were within the acceptable bioequivalence limits of 80%–125%. Thus, the carvedilol CR capsule formulation is unlikely to be affected by changes in gastric acidity that might be induced by concomitant medication known to influence gastric pH. Although this study was not performed with the final CR formulation, it is anticipated that similar results would be observed. The final formulation contains an additional carvedilol CR microparticle designed for disintegration at a higher pH; thus it is unlikely that a pH-mediated drug interaction would be observed with the final CR formulation and proton-pump inhibitors.

age over 24 hours. Exposures for both enantiomers, based on AUC, Cmax, and C␶ concentrations, are equivalent for carvedilol CR administered once daily compared with that of carvedilol IR administered twice daily. Cmax and AUC of the enantiomers of carvedilol increase in an approximately dose-proportional manner after administration of carvedilol CR over the dose range of 10 – 80 mg, indicating that the formulation provides consistent PK performance across the dose strengths proposed for marketing. The intrasubject and intersubject variability of carvedilol CR was comparable to carvedilol IR. For carvedilol CR, mean AUC and Cmax increased ⬍20% after a high-fat meal compared with a standard meal. No dose dumping was observed when carvedilol CR was given with a high-fat meal. The CR and IR formulations of carvedilol exhibited comparable steady-state PK characteristics in the target hypertension and heart failure populations. The availability of once-daily dosing is expected to improve treatment adherence and thereby enhance the effectiveness of carvedilol in routine clinical use.

Conclusion This review summarizes the PK of carvedilol after administration of a new once-daily CR formulation. The plasma concentration-time profiles for both R(⫹)- and S(⫺)-carvedilol indicate that carvedilol CR meets the CR claims made for the preparation and will provide cover-

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