Eur J Clin Pharmacol (1994) 46:523-526

© Springer-Verlag 1994

Smoking and body weight influence the clearance of chlorpromazine M. Chetty l, R. Miller 1, S. V. Moodley 2

Drug Studies Unit, University of Durban-Westville, Durban, South Africa 2 Fort Napier Hospital, Pietermaritzburg, South Africa

Received: 3 September 1993 / Accepted in revised form: 9 March 1994

Abstract. The popula t ion pharmacokine t i c parameters of ch lorpromazine (CPZ) in chronic schizophrenic patients were evaluated using 189 plasma concent ra t ion measure- ments f rom 31 patients.

A N O N M E M analysis demons t r a t ed that the clear- ance of C P Z d e p e n d e d on the patient 's b o d y weight. Ciga- rette smoking and cannabis smoking increased the clear- ance of CPZ. Chronic alcohol consumpt ion and the con- current use of anticholinergics did not appear to influence the clearance of C P Z significantly.

Key words: Chlorpromazine , Schizophrenic patients; popula t ion pharmacokinet ics , clearance, cigarette smok- ing, cannabis smoking

The m a r k e d variability in plasma drug levels in patients on fixed doses of ch lorpromazine (CPZ) has been well do- cumen ted [1-3]. This var ia t ion in p lasma levels of C P Z has been associated with the marked inter-individual dif- ferences in the response to C P Z t rea tment [3, 4-6]. M o r e information on the factors that influence the variability of plasma levels of C P Z m a y therefore assist the psychiatrist in choosing a dose of C P Z to p roduce a desired response.

In this study, the compute r p r o g r a m m e N O N M E M [7] was used to de te rmine the popula t ion pharmacokine t i c parameters of C P Z in chronic schizophrenic patients. The effect of factors such as age, weight, cigarette smoking, cannabis smoking, chronic alcohol intake and the con- comi tant use of anticholinergic agents on the clearance of C P Z was then evaluated.

Methods

Patients

Ethical approval for this study was obtained from the University of Durban-Westville.

Correspondence to: M.Chetty, Drug Studies Unit, University of Durban-Westville, Private Bag X54001, Durban 4000, South Africa

Diagnosed schizophrenic [8] in-patients of 16-55 years of age from the King George V Hospital and Fort Napier Hospital were in- cluded in the study. Informed consent was obtained from the patient, guardian or the medical superintendent. Patients presenting with an organic disorder (e.g., hepatic, renal or gastrointestinal disease) were excluded from the trial. Relapsed patients were included pro- vided CPZ or its metabolites were not present in the plasma on ad- mission to hospital.

The patient was withdrawn if there was evidence of non- compliance, administration of another antipsychotic agent, or if the patient developed severe or unacceptable adverse reactions to CPZ.

Routine physical examination and clinical laboratory tests were performed on admission of the patient.

Patients were questioned about their smoking and drinking habits. Chronic alcohol intake was regarded as the consumption of alcohol at least three times a week. Smokers were those pa- tients who smoked cigarettes daily. Cannabis smokers were those who smoked cannabis regularly. This was confirmed by urine testing. These patients were then informed about the adverse effects of cannabis and counselled by the psychiatrist and social worker.

Blood samples (10-ml) were taken via the median cubital vein. The first blood sample was taken on admission to hospital, to exclude the presence of CPZ or its metabolites in plasma. Thereafter, blood samples were taken 12h after the evening dose and either 2 h, 3 h or 4 h after the morning dose. Plasma concentrations of CPZ were then measured by an HPLC method (sensitivity of 3 ng-ml -I) that had been validated previously [9].

Data analysis

Version 3 (with double precision) of NONMEM was used to pe> form the pharmacokinetic data analysis. Previous studies indicate that first order kinetics are adequate to describe the disposition of CPZ [10]. In this study a one-compartment open model with first order absorption and elimination was chosen by selecting the appro- priate PREDPP subroutines viz. ADVAN 2, TRANS 2, and SS2. A proportional error model was used.

The significance of various factors that influence the pharma- cokinetic parameters were tested by noting the difference in the objective function values (DOBF) obtained from evaluation of the general model and ~the restricted model. A DOBF of 3.8 for 1 degree of freedom (P < 0.05) was considered statistically signi- ficant.

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Table 1. Patient demographics

Number of patients 31 Number of plasma samples 189

Age (years) 16-45 Gender 20 Male 11 Female

Weight (kg) 45-70

Cigarette Smokers (cigarette) 11 Cannabis smokers 5

Chronic alcohol intake 7

Oral contraceptives 1

Orphenadrine 4 Dosage range 200 rag- 1200 mg

Results

Patient demographics

The demographic details of the patients included in the study are presented in Table 1.

Thirty two patients were included in this study. One patient was withdrawn from the study 1 week after entry because of non-compliance.

One patient "absconded" regularly and thus an un- reliable dosing history was suspected. This patient was initially included since the accuracy of the dosing his- tory could not be verified.

(570 1 before and 18901 after fixing Ka). K, was therefore fixed at 1 h -~ in all the models that followed.

All 31 patients were included in the initial NONMEM estimation. Examination of the residual plots indicated that there were 5 plasma levels greater than 4 standard de- viations from the mean. Three of these plasma levels were measured in the patient whose dosing history was question- able and the other two levels were measured in a patient after she had been given an oral contraceptive. After exclu- sion of the first patient from the data input file, the likeli- hood of the data fit improved 2.1.10~5-fold. This patient, who might also have been a poor metaboliser, was sub- sequently excluded from the study. Exclusion of the two plasma levels from the patient who had taken the contra- ceptive improved the likelihood of the data fit 3.4.10 s4- fold. Examination of the data demonstrated a highly signi- ficant difference in the blood level before (46.4 ng. ml -~ 2.5 h after the dose and 34.1 ng. ml -~ 4 h after the dose) and after (839 ng. ml -~ 2 h after the dose and 659 ng. ml -~ 12 h after the dose) the administration of the contraceptive. Since only one patient had been on an oral contraceptive, the steps that followed excluded the two blood levels mea- sured after the patient had been given the contraceptive.

In developing the initial regression model, the in- fluence of demographic characteristics on CL and V was examined. Evaluation of the DOBF suggested that CL is related to weight. Inclusion of weight and age as a scaling factor in the regression model for volume of distribution did not improve the fit. Hence the following model was chosen as the initial regression model:

Data analysis using NONMEM

The simplest model assumed that all the patients had the same clearance (CL), volume of distribution (V), and ab- sorption rate constant (K,), with differences arising from the random inter-and intra-subject variation. The initial NONMEM estimation resulted in a value for CL/Vin h -~ (i.e., the elimination rate constant, Ke) that was greater than the absorption rate constant (Ka h-l). This indicated that the parameters had probably been transposed, ("flip- flop") because the model had been overparameterized [ll]. Insufficient data in the absorption phase could ac- count for this.

Since few plasma levels were available during the ab- sorption phase, the K, was fixed to the literature values to prevent "flip-flop". The Ka value for multiple dosing of CPZ was estimated using published values for tssm~ (time to reach peak concentration at steady state) and Ke [12]. Dahl and Strandhord [10] measured a t~mex of 2 to 4 h. Using the average literature value for the elimination rate constant (K~) of 0.028 h -~ [3], a Ka value of 1 h -1 predicts a peak concentration at 3 h [12]. K~ was there- fore fixed at i h -1. Although the population mean K~ was fixed at 1 h -~ the value of Ka for each individual was allowed to vary about the mean through the error com- ponent ni Ka [13].

Fixing the K~ value resulted in no significant change in the objective function (1726.414 before fixing K, and 1728.966 after fixing K~) but a more realistic value for V

c L = P ( i ) . wt + P(2) v = P ( 3 ) K~ = 1 h -1 (fixed)

In the steps that followed, the influence of orphena- drine, cigarette smoking, cannabis smoking and alcohol intake on the clearance of CPZ were tested. Apart from orphenadrine, all the above factors appeared to influence the CL of CPZ.

Since there was considerable overlap between ciga- rette smokers, cannabis smokers and chronic alcohol users, various combinations of the above effects were then tested in order to determine the final regression model for this population of patients. The combination of cannabis and cigarette smoking appeared to have the greatest in- fluence on the CL of CPZ.

The final regression model expressed clearance as a function of weight, cigarette smoking and cannabis smok- ing as follows:

CL = (P(1). WT + (P2))- CIG. CANN v = e(3) Ka = 1 h -1 (fixed)

where: CIG= 1 for non-smokers or is estimated for smokers; and CANN = 1 for patients who do not smoke cannabis or is estimated for smokers of cannabis. Average population pharmacokinetic parameter values for the population studied [with standard errors of the esti- mate (SEE) given in square brackets]:

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CL = [P(1). WT + P(2)] • CIG. CANN = (1.8210.21 . WT + 24.5110.011). CIG. CANN

where: average weight=57kg; CIG= 1.38 [0.35] for smokers of cigarettes and 1 for non-smokers; and CANN = 1.50 [0.28] for cannabis smokers and 1 for pa- tients not smoking cannabis.

Coefficient of variation for CL = (0.29) 1/2.100 % = 53.9 %

V = 1930 [28011 Coefficient of variation for V = (0.33) 1/2.100 %

= 57.4 %

Discussion

The estimate of 19301 for volume of distribution (33.9 1.kg -z in these patients with an average mass of 57 kg) is consistent with values of 33 1- kg-1-149 1. kg -1 re- ported in the literature [10].

The average CL measured in this population of chronic schizophrenics (average weight 57 kg) was 127 1. h -1 in the absence of other drugs, 175 1. h -1 in ciga- rette smokers and 191 1. h -z in smokers of cannabis. The combination of cannabis as well as cigarette smoking ap- peared to increase the clearance of CPZ further to 263 1. h -1. These CL values are consistent with values of 67.2 1. h -1 to 538 1. h -1 (average 257 1-h -z) measured in pa- tients (average weight 75 kg) on chronic CPZ treatment, determined by traditional pharmacokinetic methods [10]. These authors did not characterise the differences be- tween their test subjects.

Inspection of the range of CL values measured in the study by Dahl and Strandjord [10] (67-5381.h -z) indi- cates that the coefficient of variation in the present study (54%) is much smaller since some of the inter-subject variation in this study could be accounted for in the model. Expressing CL as a function of weight decreased the coefficient of variation from 71% to 68 %. The dif- ferentiation of CL between smokers and non-smokers decreased the coefficient of variation further from 68 % to 54 %.

As expected, age did not appear to influence CL in this study population (16-45 years). Including gender in the initial model did not appear to improve the model. These results are in agreement with the report by Young [14] where no significant difference was seen in plasma concentrations of CPZ and NorzCPZ in males and fe- males.

Heavy smoking has been associated with a decrease in the plasma levels of CPZ due to enzyme induction [15, 16]. In this study, cigarette smoking combined with cannabis smoking had a significant influence on clearance. It would appear that a higher dosage may be required in patients who are smokers of cannabis and cigarettes. The effects of cannabis on CPZ levels have not been documented pre- viously. Information on interactions involving cannabis is important in South Africa because of the high incidence of abuse of this drug.

Chronic ethanol exposure has been associated with an augmentation in the drug-metabolizing ability of microsomes in vitro [17]. Thus, a faster clearance is expected in chronic alcoholics. In this study, clearance was modelled for the influence of chronic ethanol in- take and the CL appeared to be increased by factor of 1.47. However, when the combined influence of ciga- rettesmoking cannabis smoking and alcohol consump- tion was examined, the influence of alcohol on CL ap- peared to be insignificant. A possible explanation for this apparent discrepancy is that the patients who consumed ethanol also smoked. To verify the influence of ethanol on the clearance of CPZ, a study on patients who use ethanol but do not smoke cannabis or cigarettes is re- quired.

The effect of antiparkinsonian/anticholinergic agents on CPZ plasma levels is controversial. Some researchers [18] have reported lowered plasma levels associated with trihexyphenidyl; others have reported no change in CPZ levels [19] and a third group have reported increased levels with trihexyphenidyl [20]. The discrepant results have been attributed to flaws in the study design and dif- ferences in subjects with respect to age and especially in chronicity of illness with its associated prolonged neuro- leptic exposure [19]. In this study, the antiparkinsonian agent, orphenadrine, did not appear to influence the clearance of CPZ. It is interesting to note that the charac- teristics of the patients in this study were similar to those in the study of Simpson et al. [19] (i.e., chronic schizophre- nics who had been taking neuroleptics previously), who found no change in CPZ levels. Rivera-Calimlim et al. [18] suggested that anticholinergic agents may interfere with the absorption rate of CPZ. This could not be tested in this study because of the lack of data in the absorption phase.

The significant change in objective function observed after the exclusion of the patient who had been given an oral contraceptive, and the marked difference in plasma concentrations before and after the oral contraceptive, warrants further studies of the interaction between oral contraceptives and CPZ. E1-Yousef and Manier [21] re- ported increased prochlorperazine and butaperazine lev- els in patients with high oestrogen levels. They proposed that oestrogens might decrease the elimination rate of phenothiazines. The observation in this study supports their proposal. This could have important therapeutic im- plications, as observed in the patient in this study. After being stabilized on CPZ, the patient experienced severe dystonia and dyskinaesia when the oral contraceptive was introduced, possibly due to the raised CPZ levels. This suggests that a dosage adjustment of CPZ might be war- ranted if a patient is given an oral contraceptive concur- rently.

The relatively small coefficient of variation (53.9 %) obtained in this study suggests that weight and smoking are important factors that influence the variation in plas- ma concentrations of CPZ between patients. The extent to which smoking may influence clearance has been "quantified". This information could be useful to the clini- cian when a dosage adjustment is indicated in a smoker.

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Fur ther studies to de termine the effects of a lcohol and oral contracept ives are warranted.

Conclusion

This study has identified some of the factors that may re- sult in p lasma level variations of CPZ. I m p o r t a n t factors that appear to influence the c learance of C P Z are the weight of the patient , cigarette smoking and cannabis smoking. Fur ther studies to investigate the clinical im- por tance o f the above observat ions are warranted.

Acknowledgements. We thank the staff of the Fort Napier and King George hospitals for their assistance during the study and the Medi- cal Research Council (SA) for the local postgraduate scholarship and research grant.

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