Detection of a drug–drug interaction on population-based phenobarbitone clearance using nonlinear mixed-effects modeling

Objective: Nonlinear mixed-effects modeling (NONMEM) was used to estimate the effects of drug–drug interaction on phenobarbitone clearance values, using 648 serum levels gathered during the routine clinical care of 349 pediatric and adult epileptic patients (age range, 0.4–33.3 years). Patients received phenobarbitone as monotherapy or in combination with either of the antiepileptic drugs carbamazepine or valproic acid. Results: The final model describing phenobarbitone clearance was CL = 52.3 · TBW^–0.567 · CO, where CL is clearance (ml · kg⁻¹ · h⁻¹), TBW is total body weight (kg) and CO is a scaling factor for concomitant medication with a value of 1 for patients on phenobarbitone monotherapy, 46.4^(−1/TBW)for those patients receiving concomitant carbamazepine and 0.642 for those patients receiving concomitant valproic acid. Phenobarbitone CL was highest in the very young and decreased in a weight-related fashion in children, with minimal changes observed in adults. This pattern was consistent whether phenobarbitone was administered alone or coadministered with carbamazepine or valproic acid. When phenobarbitone was coadministered with carbamazepine or valproic acid, phenobarbitone CL decreased compared with that in monotherapy. Its magnitudes in the presence of carbamazepine are maximal in early childhood (about 54%) and decreased in a weight-related fashion in older children, with minimal changes observed in adults. Concomitant administration of phenobarbitone and valproic acid resulted in a 35.8% decrease of phenobarbitone CL. Received: 17 February 1997 / Accepted in revised form: 21 October 1997     

Determination of phenobarbitone population clearance values for South African children

Non-linear Mixed Effects Modelling (NONMEM) was used to estimate phenobarbitone population clearance values for South African children, using 52 serum levels gathered from 32 patients during their routine care. NONMEM was also used to evaluate the influence of fixed effects such as weight, age and concomitant medication. The final model describing phenobarbitone clearance was CL=[Exp(0.0288 Wt–2.53)] M, where CL=clearance (l·h^–1), Exp=the base of the natural logarithm, Wt=patient weight (kg) and M=a scaling factor for concomitant medication with a value of 1 for patients on phenobarbitone monotherapy, 0.62 for those receiving concomitant valproate and 0.87 for those patients receiving concomitant carbamazepine or phenytoin. Mean (95% confidence interval) phenobarbitone clearance values were 7.6 ml·h^–1·kg^–1 (6.2, 9.0 ml·h^–1·kg^–1) for the monotherapy group, 5.0 ml·h^–1·kg^–1 (4.0, 6.0 ml·h^–1·kg^–1) in the presence of concomitant valproate and 6.8 ml·h^–1·kg^–1 (5.6, 8.0 ml·h^–1·kg^–1) in the presence of concomitant carbamazepine or phenytoin. These values are similar to those previously reported from both traditional and NONMEM pharmacokinetic studies.     

Pharmacokinetics and cognitive effects of carbamazepine formulations with different dissolution rates

Objective: In this study our aim was to assess pharmacokinetic effects and adverse cognitive effects of switches between generic and branded formulations of carbamazepine (CBZ). Method: Twelve patients were included in a randomized open-label, observer-blind, cross-over design with a double-baseline period, comparing three different formulations of carbamazepine in monotherapy – the innovatory branded form Tegretol and two generic forms, CBZ Pharmachemie and CBZ Pharbita. Cognitive assessment was carried out at baseline and 3 days after a cross-over. Results: Area under the curve and a number of pharmacokinetic properties (serum concentration day curves, change in serum concentration (delta scores), peak/trough concentrations and peak time) did not differ among the three CBZ formulations. Therefore, the basic assumption for this study, i.e. to test pharmacokinetic-related differences in cognitive profile, was not met. In line with these findings, none of the cognitive variables showed statistically significant differences with respect to the cognitive profile during the day. Conclusion: Switches between the investigated generic CBZ formulations and the branded product did not result in any difference in cognitive profiles. These results are not necessarily valid, though, for other generic forms of CBZ, for other types of antiepileptic drugs or for CBZ treatment in higher doses or in polytherapy. Received: 26 June 1997 / Accepted in revised form: 2 December 1997     

Effect of stiripentol on carbamazepine plasma concentration and metabolism in epileptic children

Objective: To study the relationship between the plasma concentration of stiripentol (STP), a new antiepileptic drug, and its inhibitory effect on the formation of carbamazepine epoxide (CBZE) in epileptic children treated with carbamazepine (CBZ) either alone or in combination with another antiepileptic drug. Methods: Minimum plasma concentration of antiepileptic drugs was measured before initiation of STP therapy (day 0) and on days 28 (STP 60 mg⋅kg⁻¹⋅day⁻¹) and 84 (STP 90 mg⋅kg⁻¹⋅day⁻¹) by HPLC. Results: The CBZE/CBZ plasma concentration ratio decreased exponentially with increasing minimum plasma STP concentration (r = 0.80). The asymptote of the curve allowed the calculation of the minimum plasma STP concentration required to obtain the maximum inhibitory effect, i.e. 6.7 mg⋅l⁻¹. Conclusion: The inhibitory effect of STP on CBZ metabolism expressed as the CBZE/CBZ plasma concentration ratio is dependent on STP plasma concentration, with a maximum effect at an average of 7 mg⋅l⁻¹. The present data suggest that in order to evaluate the anticonvulsant efficacy of STP as add-on therapy, the minimum plasma STP concentration should be maintained above 7 mg⋅l⁻¹ and the dosage of CBZ should simultaneously be decreased in steps by more than 50% to minimize the change in CBZ plasma concentration. Received: 27 September 1995 / Accepted in revised form: 5 January 1996     

Factors affecting oral cyclosporin disposition after heart transplantation: bootstrap validation of a population pharmacokinetic model

Objective: To determine factors affecting the population pharmacokinetics of oral cyclosporin (CsA) in cardiac allograft recipients during the first 3 weeks after surgery. Methods: Data were obtained from routine trough monitoring and from two extra samples drawn during a dosing interval on a randomly selected day. Whole blood CsA concentrations were assayed using high-performance liquid chromatography (HPLC). Approximately equal numbers of patients were prescribed Sandimmun (SAN) or Neoral (NEO) CsA formulations. Parameter values of a one-compartment kinetic model with first-order absorption and elimination were sought together with the inter-patient and intra-patient variances using the NONMEM program. Results: Improved fits resulted from using the following expression in the model to adjust apparent bioavailability as a function of post-operative day (POD): f=0.2 + 10 × ABS (POD−5)/[(POD + 7) × 60]. The CsA clearance (CL/f ) was found to be influenced by current body weight (WT). There was an absorption lag time of about 35 min with SAN, but zero lag time with NEO. Oral bioavailability (f ) was increased by about 35% with concomitant diltiazem and about 18% with NEO. The CL/f was10% higher during the daytime than at night. The final pharmacokinetic model was validated using 200 bootstrap samples of the original data. Conclusions: Using a validated population modelling approach, it was found that a number of factors influence the pharmacokinetics of CsA during the early post-operative period in cardiac transplant patients. These influences affecting oral bioavailability and clearance may need to be taken into account for maintaining appropriate concentrations of CsA in the bloodstream. Received: 29 June 1999 / Accepted in revised form: 28 April 2000     

Helicobacter pylori clearance and serum gastrin and pepsinogen I concentrations in omeprazole treatment of duodenal ulcer patients

Objective: To determine which demographic factors may influence serum gastrin and pepsinogen I (PGI) levels in duodenal ulcer patients undergoing omeprazole treatment. Methods: We conducted an outpatient-based prospective study in the Veterans General Hospital, Taipei, to investigate the pharmacological effects on patients with duodenal ulcers receiving omeprazole treatment for 4 weeks. Sixty-eight patients (61 males/7 females, aged 25–73 years) with endoscopically confirmed duodenal ulcer were included. Gastrin and pepsinogen I levels were measured before and after treatment. Demographic factors including age, sex, smoking, ulcer healing and antral Helicobacter pylori colonization/clearance were analyzed, in order to measure their probable influences on serum gastrin and pepsinogen I levels. Results: Ulcer healing was seen in 92.6% of patients while 48 (70.6%) antral clearances were seen in 66 H. pylori colonized patients at the end of trial. Omeprazole monotherapy led to a marked elevation of serum gastrin (85.8 pg · ml⁻¹, SD 32.0 pg · ml⁻¹ vs 133.9 pg · ml⁻¹, SD 71.6 pg · ml⁻¹, P < 0.01), and pepsinogen I (111.0 ng · ml⁻¹, SD 36.7 ng · ml⁻¹ vs 253.6 ng · ml⁻¹, SD 64.8 ng · ml⁻¹, P < 0.01) levels when measured on day 29. Only patients showing antral H. pylori clearance exhibited an influence on the magnitude of pepsinogen I elevation following omeprazole monotherapy (143.9%, SD 67.3% vs 78.6%, SD 51.2%, P < 0.01). Moreover, the sensitivity and specificity of serum pepsinogen I variations were plotted on a receiving operating characteristic (ROC) curve. The 140% increased pepsinogen I level yielded a maximum accuracy of 80% specificity or 50% sensitivity to predict antral H. pylori clearance. Conclusion: Antral H. pylori clearance is at least partially responsible for the omeprzaole-induced hyperpepsinogenemia I. The magnitude of hyperpepsinogenemia I probably provides a non-invasive alternative for predicting H. pylori clearance. Received: 22 August 1996 / Accepted in revised form: 1 October 1998     

Comparison of carbamazepine and oxcarbazepine effects on aminothiol levels

Objective The aim of our study was to investigate the effects of carbamazepine (CBZ) and oxcarbazepine (OXCBZ) on aminothiol levels, including homocysteine (Hcy), cysteine, and cysteinylglycine, in chronically treated patients. Methods Epileptic patients receiving CBZ or OXCBZ were recruited as part of routine clinical practice. Demographic data and concomitant medications were recorded from the patient medical file. Results Sixty patients were included in the study; 30 patients were treated with CBZ and 30 with OXCBZ. Median Hcy level was significantly higher in CBZ-treated patients (20.6 μmol/l) than in OXCBZ-treated patients (14.0 μmol/l, p < 0.0001). No correlation was evidenced between antiepileptic drugs or metabolite levels and Hcy levels for each group. Conclusions Less change observed with OXCBZ compared with CBZ on aminothiol levels could constitute an advantage for OXCBZ treatment in patients with other factors influencing Hcy levels and/or at high risk for cardiovascular diseases.     

Ketotifen pharmacokinetics in children with atopic perennial asthma

Objective: Published pharmacokinetic data on ketotifen are sparse, although it is a commonly used prophylactic agent in various allergic disorders in adults and children. The aim of this study was to assess the steady-state pharmacokinetics of ketotifen in children with atopic perennial asthma who were participating in a clinical trial. Method: The NONMEM population approach with sparse sampling was utilized. The data set consisted of 239 samples from 48 children who were randomized to receive either 1 mg or 2 mg oral ketotifen daily. Patients underwent a clinical examination and had a blood sample taken at 2-week intervals for 12 weeks. The ketotifen concentrations were measured by RIA. Results: A one-compartment model with first-order absorption was fit to the data. Volume was estimated at 394 l and clearance (CL) at 97.4 l · h⁻¹ (3.6 l · h⁻¹ · kg⁻¹). Weight or body surface area were the most influential covariates for explaining interindividual variability in CL. The 2-mg dose appeared to have a relative bioavailability of 85% of the 1-mg dose. Conclusion: Children have a faster clearance of ketotifen than adults and would therefore require a higher dose per kilogram body weight to give comparable steady-state levels. Received: 15 September 1996 / Accepted in revised form: 31 January 1997     

Fluvoxamine is a potent inhibitor of tacrine metabolism in vivo

Objective: In vitro studies have shown that tacrine is metabolized by cytochrome P4501A2 (CYP1A2). One of the monohydroxy-metabolites has been incriminated with tacrine-induced hepatotoxicity. The aim of this study was to establish whether the potent CYP1A2 inhibitor fluvoxamine in clinically relevant doses could inhibit tacrine metabolism. Methods: Eighteen healthy young men were enrolled in an open, randomized crossover study. In the first study period a single oral dose of tacrine 40 mg was given. In the second period the volunteers were randomized to maintenance doses of fluvoxamine 50 or 100 mg per day, and a single oral dose of tacrine 20 mg was given. Results: Fluvoxamine was found to be a very potent inhibitor of tacrine metabolism. A fractional decrement in tacrine clearance of approximately 85% was found with both fluvoxamine doses, which was in good agreement with a prediction based on in vitro data. The medians of the steady-state concentration of fluvoxamine were 43 nM (range 25–49) and 70 nM (range 44–124) in the 50 mg per day and 100 mg per day groups, respectively. The steady-state concentration of fluvoxamine correlated with the fractional decrement in tacrine clearance (Spearman R_s = 0.53, P < 0.05). Modest, but statistically significant, reductions in the formation of the metabolites 1- and 2-hydroxytacrine were found during concomitant fluvoxamine treatment. Conclusion: Fluvoxamine at clinically relevant doses is a potent inhibitor of tacrine metabolism. This interaction is very likely to have clinical relevance. Whether concomitant fluvoxamine treatment reduces tacrine-induced hepatotoxicity needs further study. Received: 16 September 1998 / Accepted in revised form: 27 January 1999     

Pharmacokinetics of cloxacillin in patients undergoing hip or knee replacement

Objective: The pharmacokinetics of cloxacillin was investigated in 14 men and 24 women undergoing cemented hip (n = 19; age range 56–90) or knee replacement surgery (n = 19; age range 51–84) for osteoarthritis. Cloxacillin 1 g was given intravenously as a bolus dose at the induction of anesthesia, and plasma samples and urine were collected for 6 h. Drug levels were determined using HPLC. Results: Preoperative serum creatinine levels were 84 μmol · l⁻¹ in hip patients and 72 μmol · l⁻¹ in knee patients. The calculated values for creatinine clearance were 63 and 85 ml · min⁻¹ · 1.73 m⁻², respectively. Total clearance of cloxacillin was 134 ml · min⁻¹ · 1.73 m⁻² in eighteen evaluated patients undergoing hip replacement, and 162 ml · min⁻¹ · 1.73 m⁻² in eighteen patients undergoing knee surgery. Renal clearance was 72 and 79 ml · min⁻¹ · 1.73 m⁻², respectively. Non-renal clearance was 57 ml · min⁻¹ · 1.73 m⁻² in hip patients and 77 ml · min⁻¹ · 1.73 m⁻² in knee patients. Renal clearance of cloxacillin correlated with the estimated creatinine clearance (r = 0.652). Although women received higher doses than men (median 2.02 vs 2.32 mmol · 1.73 m⁻²), there were no sex differences in clearance corrected for body surface area. Conclusion: Total clearance of cloxacillin was lower in patients undergoing hip replacement than in patients undergoing replacement of the knee, but there was no difference between men and women. Received: 7 May 1996 / Accepted in revised form: 15 October 1996     

Pharmacoepidemiologic investigation of a clonazepam-carbamazepine interaction by mixed effect modeling using routine clinical pharmacokinetic data in Japanese patients.

Nonlinear mixed effects modeling was used to estimate the effects of clonazepam-carbamazepine interaction on clearance values using 359 serum levels gathered from 183 pediatric and adult epileptic patients (age range, 0.3-26.8 years) during their clinical routine care. Patients received the administration of clonazepam and/or carbamazepine. The final model describing clonazepam clearance was CL = 179.0 x TBW(-0.231) x 1.22(CBZ), where CL is total body clearance (mL/kg/h) and TBW is total body weight (kg); CBZ = 1 for concomitant administration of carbamazepine and CBZ = zero otherwise. The final model describing carbamazepine clearance was CL = 92.7 x TBW(-0.394) x DOSE(0-397) x 0.795(CZP), where DOSE is the daily dose of carbamazepine (mg/kg/day); CZP = 1 for concomitant administration of clonazepam and CZP = zero otherwise. Concomitant administration of clonazepam and carbamazepine resulted in a 22% increase in clonazepam clearance and a 20.5% decrease in carbamazepine clearance.     

Population Pharmacokinetic Modeling of Steady State Carbamazepine Clearance in Children, Adolescents, and Adults

Carbamazepine (CBZ) clearance decreases from childhood to adulthood and the factors determining this change could include age, size, autoinduction, or maturational changes. This study aims to describe the population pharmacokinetics of CBZ in children and young adults and test the hypothesis that CBZ clearance correlates with weight, surface area, and age. CBZ therapeutic drug monitoring data (sparse data) were collected from child and adult epileptics, and rich data were obtained from a bioequivalence study of CBZ in young adults. Population pharmacokinetic analysis was performed using NONMEM V. Forward stepwise, multiple regression was performed on the covariates. Bootstrap validation was performed. A total of 946 observations from 91 subjects, ages 0.7–37 years, were collected and analyzed. A one-compartment, first-order absorption and elimination model, with exponential interindividual error and additive residual error models was developed. The population model was: Clearance (Lhr ^–1)=((2.24 · Surface area (m ²))+(0.047 · Dose (mg · kg ^–1)); Volume of distribution (L)=0.37 · weight (kg); Absorption rate constant=0.013 (hr ^–1). CBZ clearance increased with surface area and dose.     

Population pharmacokinetics of free carbamazepine in adult Omani epileptic patients

OBJECTIVE: The aim of this study was to define the pharmacokinetic profile of free carbamazepine (F-CBZ) in adult Omani epileptic patients in order to improve on dosing schedules through population pharmacokinetic analysis using the NONMEM program. METHOD: Steady-state trough F-CBZ serum concentrations, carbamazepine (CBZ) dosing history and associated information were collected prospectively. RESULTS: Forty-eight patients with two or more available F-CBZ serum concentrations (total of 149 dose/serum concentration pairs) met our inclusion criteria. Patients were taking CBZ (200-1200 mg/day) in monotherapy. The analysis assumed a one-compartmental open model with first-order absorption and elimination. The apparent clearance (CL/F) and apparent volume of distribution (V/F) and their interindividual variabilities were estimated using the program. The population estimates for clearance (CL; modelled independently of dose) and volume of distribution were 13.2 +/- 0.6 l/h and 525 +/- 44 1, respectively. However, CL increased as a function of dosing rate and consequently was modelled as a linear function of steady-state concentration. In order to validate these results, the predictions of the population model were tested against data from 13 further patients subjected to the same inclusion criteria but who were not included in the original analysis. The predictions were good, being unbiased (P=0.31), and had an average deviation from the observed values of 18%. CONCLUSION: In order to establish steady-state dosage regimens, a population pharmacokinetic model is proposed, based on the patient's dose, to estimate the individual CL for an Omani epileptic patient receiving CBZ in monotherapy.     

The pharmacokinetics of pravastatin in patients on chronic hemodialysis

Objective: The single-dose and steady-state pharmacokinetics of the HMG CoA reductase inhibitor pravastatin and its two metabolites, SQ 31 906 and SQ 31 945, were evaluated in 12 hemodialysis patients. A single 20-mg i.v. dose was employed, followed by daily oral dosing of 20 mg over four hemodialysis intervals. Results: No statistical differences in the pharmacokinetics of pravastatin or SQ 31 906 were evident when comparing the first and last days of oral dosing with pravastatin. The pharmacokinetic parameters of pravastatin and SQ 31 906 were similar to those of healthy volunteers. SQ 31 945, the inactive polar metabolite, did accumulate in dialysis patients, as evidenced by an accumulation index of 1.7 ± 1.0. Although metabolic clearance is the predominant mode of elimination of pravastatin, hemodialysis clearances of pravastatin, SQ 31 906 and SQ 31 945 will contribute to total body clearance since dialytic clearance ranged from 40 to 80 ml · min⁻¹. Conclusion: Pravastatin can be safely administered in the usual dosages to subjects with renal failure on hemodialysis and no change in dosing is necessary. Received: 7 January 1997 / Accepted in revised form: 12 May 1997     

A pharmacokinetic interaction between carbamazepine and olanzapine: observations on possible mechanism

Objective: Olanzapine is a novel antipsychotic, which is effective against both the positive and negative symptoms of schizophrenia and causes fewer extrapyramidal adverse effects than conventional antipsychotics. The purpose of the present study was to assess the potential for a pharmacokinetic interaction between olanzapine and carbamazepine, since these agents are likely to be used concomitantly in the treatment of manic psychotic disorder. Method: The pharmacokinetics of two single therapeutic doses of olanzapine were determined in 11 healthy volunteers. The first dose of olanzapine (10 mg) was taken alone and the second dose (10 mg) after 2 weeks of treatment with carbamazepine (200 mg BID). Measurement of urinary 6-hydroxycortisol/cortisol excretion was used as an endogenous marker to confirm that induction of CYP3A4 by carbamazepine had occurred. Results: The dose of olanzapine given after a 2-week pre-treatment with carbamazepine was cleared more rapidly than olanzapine given alone. Olanzapine pharmacokinetic values for C_max and AUC were significantly lower after the second dose, the elimination half-life was significantly shorter, and the clearance and volume of distribution were significantly increased. Conclusion: Carbamazepine has been shown to induce several P450 cytochromes including CYP3A4 and CYP1A2. Since CYP1A2 plays a role in the metabolic clearance of olanzapine, the interaction may be attributed to induction of CYP1A2 by carbamazepine, leading to increased first-pass and systemic metabolism of olanzapine. The interaction is not considered to be of clinical significance because olanzapine has a wide therapeutic index, and the changes in plasma concentration of olanzapine are within the fourfold variation that occurs without concern for safety in a patient population. Received: 22 July 1997 / Accepted in revised form: 1 June 1998     

Population pharmacokinetics of caffeine in premature neonates

Objective: To determine population pharmacokinetic parameters of caffeine in premature neonates. Methods: This population analysis was done using 145 serum concentration measurements gathered from 75 hospitalized patients during their routine clinical care. The data were analysed by use of NONMEM (mixed effects modelling) according to a one-compartment open model with either zero or first-order absorption and first-order elimination. The effect of a variety of developmental, demographic and clinical factors (gender, birth weight, current weight, gestational age, postnatal age, postconceptional age and concurrent treatment with phenobarbital and parenteral nutrition) on clearance and volume of distribution was investigated. Forward selection and backward elimination regression identified significant covariates. Results: The final pharmacostatistical model with influential covariates were as follows: clearance (ml · h⁻¹) =5.81 · current weight (kg) + 1.22 · postnatal age (weeks), multiplied by 0.757 if gestational age ≤ 28 weeks and 0.836 if the current primary source of patients' nutrition is parenteral nutrition, and volume of distribution (ml) = 911 · current weight (kg). The interindividual variability in clearance and the residual variability, expressed as coefficients of variation, were 14.87% and 18.44%, respectively. Due to the lack of information on the data set we were unable to characterize the interindividual variability for volume of distribution. Conclusion: In this study, which involved on average only two serum concentrations of caffeine per patient, the use of NONMEM gave us significant and consistent information about the pharmacokinetic profile of caffeine when compared with available bibliographic information. Additionally, parenteral nutrition and low gestational age (≤ 28 weeks) may even come to be considered as risk factors, and their presence may serve as an indicator of the need for periodic monitoring of caffeine concentrations in premature infants. Received: 27 July 1996 / Accepted in revised form: 26 November 1996     

Detection of Carbamazepine-induced Changes in Valproic Acid Relative Clearance in Man by Simple Pharmacokinetic Screening

Selecting the optimum dose of valproic acid is difficult because the pharmacokinetics are complicated by inter-patient variability and by effects arising as a result of co-administration with other antiepileptic drugs. The multiple peak approach has been used to evaluate the effect of age, total body weight, dose, gender and co-medication (carbamazepine-induced change) on population estimates of valproic acid relative clearance. Routine clinical pharmacokinetic data (n = 479) were collected from 207 epilepsy patients on combination therapy. The data were analysed by a simple steady-state pharmacokinetic model with the use of NONMEM, a computer program designed for population pharmacokinetic analysis that enables pooling of data. NONMEM estimates suggested that the rate of valproic acid clearance in patients receiving concomitant administration of valproic acid and carbamazepine decreased non-linearly with increasing total body weight in the maturation process, and increased non-linearly with increasing valproic acid dose. The clearance in females was 5.7% less than in males. NONMEM estimates also suggested that the rate of valproic acid clearance increased non-linearly with increasing carbamazepine dose. Concomitant administration of valproic acid and carbamazepine with other antiepileptic drugs resulted in an increase in valproic acid clearance of 10%. The final regression model of valproic acid relative clearance was CL = 606TBW^0.168 ×DOSE^0.414 × CBZDOSE^0.095 × 0.943^GEN × 1.10^CO, where CL is the clearance (mL kg^? h^?), TBW is the total body weight (kg), DOSE is the dose of valproic acid, CBZDOSE is the dose of carbamazepine, GEN = 0 for males and 1 for females and CO = 0 for concomitant administration of valproic acid and carbamazepine and 1 for concomitant administration of valproic acid and carbamazepine with other antiepileptic drugs. This technique can be used to estimate the pharmacokinetic parameters of a population from sparse data collected during routine clinical care and to determine the extent to which patient characteristics influence drug pharmacokinetics.     

Pharmacokinetics of low doses of methotrexate in patients with psoriasis over the early period of treatment

Objective: The aim of the present study was to investigate the pharmacokinetics and pharmacodynamics of low-dose methotrexate (MTX) in the early phase (3 months) after the start of antipsoriatic therapy. Methods: Ten male and female psoriatic patients who failed to respond to previous conventional therapy were treated with 15 mg oral MTX once per week. The pharmacokinetics in plasma and the urinary excretion of MTX and 7-hydroxymethotrexate (7-OH MTX) were investigated after doses 1, 5 and 13 (corresponding to phases I, II and III, respectively). On the same occasions, MTX accumulation in erythrocytes obtained before MTX administration was investigated. Pharmacodynamics of MTX were evaluated using the psoriasis area and severity index (PASI) score. Results: There were marked intersubject differences (range of coefficients of variation 34.9–76.3%) in the area under the curve (AUC), peak concentration (C_max) and clearance (CL) of MTX. Total CL was proportional to renal clearance (CL_R) (r ² = 0.735, P < 0.0001) which accounted for 73 (19)% of the former. There was a strong linear relationship (r ² = 0.819, P < 0.0001) between CL of MTX and creatinine clearance. Within 48 h of drug administration, the urinary excretion of MTX was 46–99% of the dose, while that of 7-OH MTX was 1.5–8.6%. In 8 of 10 patients, more than 70% of the MTX dose was recovered. No intraindividual variations of MTX kinetic parameters during treatment were observed. MTX concentrations in erythrocytes reached the steady-state concentration in the range 40.7–170 nmol · l⁻¹ after 2 months of therapy. Pharmacodynamic measurement versus pharmacokinetics revealed a significant inverse relationship between PASI score and MTX AUC (r _s = −0.912, P < 0.002) and between PASI score and erythrocytic MTX (r _s = −0.988, P < 0.002). Conclusion: The relationship between MTX pharmacokinetics (AUC or erythrocytic MTX) and pharmacodynamics (PASI score) may exist. It is likely that the efficacy of psoriasis therapy with MTX could be improved by adjusting the dose according to plasma concentrations obtained after the first MTX administration. Received: 15 April 1997 / Accepted in revised form: 18 July 1997     

Investigation into the age-dependence of the pharmacokinetics of cyproterone acetate in healthy male volunteers

Objective: To investigate a possible age-dependence of the pharmacokinetics of cyproterone acetate following single oral administration. Methods: Twenty eight healthy men between 22 and 74 years of age received a single oral dose of 100 mg cyproterone acetate. The pharmacokinetic parameters, area under the serum concentration-time curve, apparent volume of distribution, apparent clearance, terminal half-life and the concentration ratio of 15β-hydroxy-cyproterone acetate/cyproterone acetate were examined for possible age-dependence using regression analysis. Results: The values of area under the serum level-time curve showed high interindividual variability and were not related to age. With regard to apparent clearance and volume of distribution, decreasing and increasing values, respectively, were observed with increasing age. There was also a clear dependence of the terminal half-life on age. Elderly men had values about two times higher (95 h) than men belonging to the younger age groups (45 h). The mean concentration ratio of 15β-hydroxy-cyproterone acetate/cyproterone acetate was 0.8 (0.3) and showed no age-dependent change. Conclusions: Apparent clearance and apparent volume of distribution of cyproterone acetate showed age-dependent changes. Combined, the two effects cause a clear age-dependence of the terminal half-life of cyproterone acetate. An age-related reduction in liver volume is thought to be mainly responsible for the decrease in hepatic clearance with age. Chronic daily administration of the drug to elderly men may therefore lead to somewhat higher steady-state concentrations in the serum than in young men receiving the same dose. Received: 9 December 1996 / Accepted in revised form: 10 April 1997     

Pharmacokinetics of intravenous N-acetylcysteine in pre-term new-born infants

Background: Reactive oxygen species have been considered to play a role in several clinical complications in pre-term infants. The aim of this study was to determine the pharmacokinetics of intravenous N-acetylcysteine in pre-term neonates. This information is needed to evaluate the use of N-acetylcysteine as an antioxidant in this patient group. Methods: N-acetylcysteine was infused intravenously in ten patients (gestational age 24.9–31.0 weeks, weight 500–1384 g) for 24 h (3.4–4.6 mg/kg/h), starting 2.0–11.2 h from birth (study I) and in six patients (gestational age 25.9–29.7 weeks, weight 520–1335 g) for 6 days (0.3–1.3 mg/kg/h), starting at the age of 24 h (study II). Arterial plasma N-acetylcysteine and cyst(e)ine concentrations were determined from timed samples taken during (study I and II) and after (study I) the N-acetylcysteine infusion. Results: In study I, the mean elimination half-life of N-acetylcysteine was 11 h (range 7.8–15.2 h). The mean plasma clearance of N-acetylcysteine was 37 ml/kg/h (range 13–62 ml/kg/h) and the mean volume of distribution was 573 ml/kg (range 167–1010 ml/kg). The plasma clearance and volume of distribution correlated with weight (r = 0.81, P < 0.01, and r = 0.78, P < 0.01, respectively) and with gestational age (r = 0.71, P < 0.05, and r = 0.64, P < 0.05, respectively). In study II, the steady-state concentration of N-acetylcysteine was reached in 2–3 days in five of six patients during a constant infusion. Conclusions: The pharmacokinetics of N-acetylcysteine in pre-term infants depend markedly on weight and gestational age. The elimination of N-acetylcysteine is much slower in pre-term new-borns than in adults. Received: 12 April 1999 / Accepted in revised form: 18 August 1999