Pharmacokinetics of quinine in obesity

TRANSACTIONSOFTHEROYALSOCIETYOFTROPICALMEDICINEANDHYGIENE(2000)94,425-428

Pharmacokinetics

of quinine

in obesity

‘Fact&y ofScience and S. Viriyayudhakorn’, S. ThitiarchakuP, S. Nachaisit’, P. C. Ho3 and S. Wanwimolruk3 Technology, and 2Faculty of Medicine, Thammasat University, Bangkok, Thailand; 3School of Pharmacy, University of Otago, Dunedin, New Zealand Abstract Obesity can modify the pharmacokinetics of lipophilic drugs. As quinine is a lipophilic drug, this study was conducted to determine whether the pharmacokinetics of quinine is altered in obese subjects. Nine obese Thai men were compared with 8 age-matched lean men. After an oral dose of quinine had been given to the men, plasma quinine concentrations were measured up to 48 h after the dosing. Mean peak plasma quinine concentration in the obese group was significantly lower than that observed in the controls (4.0 f 0.8 vs 5.0 * 0.3 mg/L, P < 0.01). There were no significant differences in time to reach the peak plasma concentration, half-life and total clearance of quinine between the 2 groups. The mean clearances of quinine normalized to the ideal bodyweight (IBW) in the obese and the control groups were not significantly different (0.091 f O-018 vs 0.091 f 0.024 Ilhlkg IBW, P > 0.05). As there are similarities in the total clearance and the clearance of quinine based on IBW, the maintenance dose of quinine should be given to obese patients on the basis of ideal bodyweight, not on total bodyweight. Keywords: quinine, obesity, pharmacokinetics, antimalarial drug Introduction Quinine, one ofthe oldest drugs in the pharmacopoeia, is widely used for the treatment of severe and complicatedmalaria (WERNSDORFER,~~~~;WHITE,~~~~). A recent study has shown that the malaria parasites in tican patients are still very sensitive to quinine. A dose of 10 mg quinine/kg is effective for the treatment of acute falcipamm malaria without augmenting therapy with any other drugs such as tetracycline or sulfadoxine-pyrimethamine (BABALOIA et al., 1998). Quinine is also commonly prescribed for the elderly to prevent nocturnal cramp. Obesity is common, especially in the USA where the prevalenceofobesityhasincreasedtiom 25.4% in 197680 to 33.3% in 1988-91 (KUCZMARSKI et al., 1994). Current drug dosing recommendations are usually based on published pharmacokinetic data from studies in subjects or patients of normal bodyweight. These recommendations may be inaccurate when applied to obese patients owing to physiological changes of obesity, which affect the pharmacokinetics of drugs (CHEYMOL, 1993). Many studies have shown that obesity affects the pharmacokinetics and metabolism of highly lipid-soluble drugs (CHEYMOL. 1993; KOTLYAR & CARSON. 1999). As &&ine is a iipophilic drug and has low’hepatic clearance with a narrow therapeutic index, significant alterations in the pharmacokinetics of quinine in obese individuals might have clinical implications with respect to dosage regimens in obese patients. Therefore, the present study was conducted to determine the effects of obesity on the pharmacokinetics of quinine after a single oral dose of quinine. Methods The study was approved by the Human Ethics Committee, Thammasat University, Pathumthani, Thailand. Subjects Nine obese men (aged 18-49 years) and 8 male lean (control) volunteers (aged 19-41 years) participated in the study. All subjects gave written informed consent. They were non-smoking Thai healthy volunteers. The studied men had no history of drug hvoersensitivitv and had not taken any medication for 2we&s before eniering and during the study. They were determined to be healthy by medical history, physical examination and blood

chemistry

tests.

for correspondence: Dr Sompon Wanwimolruk, School of Pharmacy, University of Otago, P.O. Box 913, Dunedin, New Zealand; phone +64 3 479 7293, fax

Address

+64 3 479 7034,

e-mail [email protected]

Ideal bodyweight (IBW) was defined as: IBW (male) = 49.9 kg + 0.89 kg/cm above 152.4 cm height (GREENBUTT et al., 1984; SCHWARTZ et al., 1991). The percentage IBW (% IBW) was calculated as the ratio of total bodyweight to IBW. Subjects were classified as obese if their total bodyweight was 125% or more of IBW. Mean % IBW f standard deviation (SD) was 143 f 16 in the obese subjects, range 123- 169, and 95 & 7 in the controls (range 88-l 10, Table 1). Owing to difliculty in the recruitment of obese subjects, 1 volunteer with 123% IBW was included in the obese group. Study design After an overnight fast, all subjects received an oral dose of 600 mg quinine sulphate with a glass of water. Quinine sulphate tablets (Quinoc” 300 mg) were kindly supplied by Douglas Pharmaceutical, Auckland, New Zealand. Subjects remained fasting for 3 h after drug administration. Venous blood samples were collected into heparinized tubes before the dose, and at 0*25,05, 0.75, 1, 1.5,2,25,3,4,6,8, 10, 12,24,30,36 and 48 h after dosing. Blood samples were centrifuged, and the plasma was separated. The plasma samples were kept frozen at -20°C until assayed. Analysis of samples The concentration of quinine in plasma samples was determined by high-performance liquid chromatography as previously described (ZOEST et al., 1990). The lower limit of detection of the assay was 0.02 mg/L and the coefficient of variation averaged <8%. Data analysis Plasma quinine concentrations were plotted semilogarithmically against time. The elimination rate constant (k) was e&&ated by linear least-squares regression analvsis of the terminal oortion of the concentrationtimeprofile. The area unher the plasma drug concentration-time curve (AUC) from zero to the last measured concentration (AU&&, total AUC, i.e. from zero to infinity (AUC,), and elimination half-life (tliz) were estimated by using the standard equations as described previously (WANWIMOLRUK et al., 1993). Quinine was assumed to be completely absorbed and the apparent oral clearance (CL) was estimated as CL = dose/ AU&, . Plasma drug concentration-time data were plotted and inspected to identify maximum (peak) concentration (C,,) and time to reach the peak concentration (L,) . All results are presented as mean values f SD. Comparisons of uarameters between control and obese groups were performed by an unpaired t-test for normally distributed sample means. When the samples were

S.VIRIYAYUDHAKORN

426

Table

1. Subject

demographics

Parameter

and quinine

dose based on bodyweight

Control men (n = 8)

Age (Yea=)

ETAL.

Obese men (n = 9)

Height (cm)

164f8

25k 10 171 i 6

ziY(gf % IBW Quinine dose/kg TBW (mgkg) Quinine dose/kg IBW (mgkg)

57*5 60f7 95*7 8.8 f0.9 8-3 f 1.0

96f16* 67 f6 143&16* 5.3 &O-8* 7.5 iz 0.6

29zt6

Values are mean f SD. TD3~otc$ bodyweight; IBW, ideal bodyweight. . . non-normally distributed, the Mann-Whitney test was used. Statistical significance was defined as P < O-05.

quinine doses based on a milligram per kilogram IBW were not significantly different between the 2 groups. The Figure is a plot of the mean plasma quinine concentrations as a function of time in obese and control groups. In both groups, peak plasma concentrations (C,,) of quinine were rapidly achieved within approximately 2 h and a monoexponential decline of concentrations in the terminal (elimination) phase was observed. Table 2 lists the derived pharmacokinetic parameters of quinine in the 2 groups. Mean C,, in the obese subjects was significantly lower than that observed in the controls (4.0 f 0.8 mg/L vs 5.0 & 0.3 mg/L, P < 0.01). Mean values of t,, half-life (+) and total AUC (AUC,) were similar between the 2 groups. Absolute CL of quinine in the obese group was not significantly different from that observed in the control group (Table 2). When CL was normalized by the TBW, there was a significant difference (P < 0.05) in this parameter between the obese and the control groups. However, when CL was normalized by IBW, the difference between the 2 groups was not statistically significant (Table 2).

Results Statistical analysis of the subjects’ demographics did not reveal significant differences between obese and lean (control) subjects according to age, height and IBW (Table 1). Mean total bodyweight (TBW) of the obese group was significantly greater than that in the controls (96 f 16 kg vs 57 f 5 kg, P< 0.001). The TBW of obese subjects was 143 & 16% of the IBW, whereas that of control subjects was 95 f 7% of IBW. Because the obese subjects weighed more than the control individuals, the doses of quinine administered to this group were significantly less than to the controls, on a milligram per kilogram TBW basis (Table 1). In contrast, the

Discussion Quinine is still the most widely used antimalarial drug for treatment of severe malaria in the world. There were no pharmacokinetic data on quinine until the late 1970s when modern analytical methods became available (WHITE, 1985). Many pharmacokinetic studies of quinine have been conducted in either healthy volunteers or patients with normal bodyweight. However, quinine pharmacokinetics can be influenced by a number of factors (WANWIh4 OLRUK et al., 1995; WHITE, 1985). For instance, the metabolic and renal clearance of quinine are reduced in patients with malaria (WHITE et al., 1982), whereas the elimination of quinine is enhanced in cigarette smokers (WANWIMOLRUK et al., 1993). Optimizing the drug dosage proportionately for bodyweight appears reasonable. However, in practice, adjustments forbodyweight are made only for children or for adults who are petite, emaciated or obese (ROWLAND & TOZER, 1989). For quinine, there is no information on

0 0

8

16

24 Time (h)

32

40

48

Figure. Plasma quinine concentration (mean and SD bar) vs time profiles after a single oral dose of 600 mg quinine sulphate in obese and lean/control (A-A, n = 8).

subjects. Obese (-0,

Table 2. Derived pharmacokinetic single oral dose of 600 mg quinine Quinine pharmacokinetic parameters

Cm,(w&l I AIJC %?’ (mg.h/L) CL(~1

n = 9); lean

parameters sulphate

of quinine

in the lean (control)

Lean men (n= 8)

o-3 fItO-9 f 3.1 98zt33 5.5 * 1.4 0.096 zt0.023 5.0 2.4 12-5

CL normalized TBW (L/h/kg TBW) 0.091 & 0.024 CL normalized (IJh/kg IBW) Values are mean * SD. NS, not significant; TBW, total bodyweight; IBW, ideal bodyweight. For definitions

of the pharmacokinetic

parameter abbreviations,

see ‘Data analysis’.

and the obese men following Obese men (n = 9)

4.Ozt 0.8 2.1 0.8 11.9 3-2

zt f 85zt18 6.0 * 1.2

0.064 kO.016

0.091 + 0.018

Significance P< 0.01

:z E P-=z 0.05 NS

a

PHARMACOKINETICS OF QUININE IN OBESITY whether the dosage of quinine should be modified for obese patients. The calculated pharmacokinetic parameters in the controls (healthy volunteers) from the present study are in agreement with those previously reported in Thai men (WHITE et al., 1983; WANWIMOLRUK et al., 1993, 1995; KRISHNA & WHITE, 1996; VIRIYAWDHAKORN & WANWIMOLRUK, 1996). The volume of distribution (Vd) of quinine could not be estimated from the present study because the drug was given orally. In the absence of an intravenous dose, Vd cannot be calculated accurately and confidently without making assumptions (ROWLAND & TOZER, 1989). Despite this, the lower mean C,, value observed in the obese subjects may imply an increase in the Vd of quinine in the obese individuals. As quinine is a lipophilic hrug, it is logical to expect the drug to distribute into the excess adipose tissue in obese subjects. This view is supported by our finding that there was a strong negative correlation between the C,,values and the TBW (r = -0.701, P < 0.005) when the data from both groups were combined (n = 17). Similar findings were also reported previously for other lipidsoluble drugs (such as theophylline, phenytoin, diazepam and lignocaine) in which the volume of distribution was increased in obese subjects (GAL et al., 1978; ABERNETHY & GREENBLATT, 1985; CHEYMOL, 1993). The lower C,,, in the obese group could suggest that a higher loading dose of quinine is required for the obese patients. Alternative explanations for the lower C,, values observed in the obese subjects are that the absorption of quinine is incomplete in these individuals. To our knowledge, there is no information on whether obesity affects drug absorption. CHEYMOL (1993) stated that drug absorption does not seem to be influenced by obesity. The primary aim of this study was to determine whether obesity affects pharmacokinetic parameters (most importantly 2 parameters, i.e., Vd and CL) of quinine. The results obtained not only apply to Thai patients but should also be applicable to any obese oatient. There are many cases of obese Thai and western people who came back from trekking with malarial infection (S. Thitiarchakul. Thammasat Universitv Hospital, BaAgkok, personal *communication). It i’s well recognized that, with globalization, there is an increasing trend of western people visiting malaria-endemic countries such as those in Africa. South America and SouthEast Asia, and returning hbme with malaria, so-called ‘traveller’s malaria’ (BRADLEY & WARHURST, 1994; WHO. WHO website: www. who. At). Thus. it is essential to kndw whether obesity affects th& 2 pha*rmacokinetic parameters (Vd and CL) of quinine, as obesity is common in the western countries (KUCZMARSKI et al., 1994) and quinine is also prescribed for the treatment of night cramp in the elderly. Although obese Thai patients with malaria are not often seen, changes in the current dietary style of the younger generationi in Thailand may increase the orevalence of obesitv. The findings of this study are of ihportance as there may be an increase in the Vd of quinine in obese individuals, and the Vd is a pharmacokinetic parameter used to estimate the loading dose of drugs. Therefore, if it is true that the Vd of quinine is increased in obese patients, the current recommended loading dose needs to be modified according to the standard pharmacokinetic equation (ROWLAND & TOZER, 1989; BIRKE~, 1998), i.e., loading dose = Cp. Vd, where Cp is the desired plasma drug concentration and Vd is the volume of distribution. Furthermore, the clinical implications of our findings for optimization of quinine dosing could be applied to obese patients with malaria. An example is the current recommendation of loading dose for the treatment of previously untreated malaria patients. It has been suggested that the initial loading dose of quinine (7 mg/kg of salt) should be given by a slow infusion, followed by 10 mg/kg infusion over 4 h (KRISHNA & WHITE, 1996

427

and references therein). Clinicians should be aware of this implication and should review the appropriate loading dose of parenteral quinine in obese patients with malaria, especially as the plasma quinine concentration is not routinely monitored. Quinine is also a drug with narrow therapeutic index and known to induce concentration-dependent prolongation of the QT interval as a serious side-effect (KRISHNA & WHITE, 1996 and references therein). Clinical studies on obese patients are worth carrying out. The present study showed that the dosage of quinine based -on TBW- in the control &an) group (8.8 & 0.9 me/kg. Table 1) is similar to the usual iecommendeud Gintenance’dose of quinine in adults, 10 mg/kg (WHITE et al., 1983). In contrast, the mean quinine dose based on TBW in the obese group (5.3 * 0.8 mg/kg, Table 1) was significantly less than that given to the controls (P < 0.001). If this maintenance dose is used in obese individuals, in terms of mgi kg TBW, clinicians may respond by increasing the dosage of quinine according to their TBW. Such a recommendation would be wrong because the results from the present study have shown that the mean total (absolute) clearances of quinine are similar for the obese and the control groups (6.0 & 1.2 vs 5.5 * 1.4 L/h, P > 0.05, Table 2). In fact, the clearance of quinine in the obese group, when normalized to the IBW, was not significantly different from that observed in the control group. The similarity of clearance values between the 2 &oups indicates tha; the ability of the liver to eliminate auinine is not affected bv obesitv. Therefore, the maint’enance dose of quinine for obese patients-should be given on the basis of patient’s IBW, not based on the TBW. In summary, on the basis of this information we recommend that the maintenance dose of quinine in obese patients be based on ideal bodyweight, not total bodyweight. Otherwise, unnecessary adverse drug reactions may occur if the maintenance dose is given according to obese patients’ total bodyweight. Acknowledgement

The study was supported by research funding from Thammasat University, Pathumthani, Thailand.

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1 Announcements

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Received 12 November 1999; revised 20 March 2000; acceptedfor publication 6 April 2000

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