Influence of CYP2B6 516G>T polymorphism and interoccasion variability (IOV) on the population pharmacokinetics of efavirenz in HIV-infected South African children.

OBJECTIVE: To investigate the influence of CYP2B6 516G>T polymorphism, as a covariate, and of interoccasion variability (IOV) on the oral clearance (CL/F) of efavirenz (EFV) in treatment-naïve black South African children over a period of 24 months post-antiretroviral therapy (ART) initiation. METHODS: HIV-infected black children (n = 60, aged 3-16 years), with no prior exposure to ART, eligible to commence ART and attending an outpatient clinic were enrolled into this study. Blood samples were taken at mid-dose interval at 1, 3, 6, 12, 18 and 24 months post-ART initiation. EFV plasma samples were determined with an adapted and validated LC/MS/MS method. Genotyping of the CYP2B6 G516T single nucleotide polymorphism (SNP) was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). NONMEM was used for the population pharmacokinetic modelling. RESULTS: EFV concentrations below 1 µg/mL accounted for 18% (116/649), EFV concentrations >4 µg/mL accounted for 29.5% (192/649) and concentrations within the therapeutic range (1-4 µg/mL) represented 52.5% (341/649) of all the samples determined. The covariates age, weight and CYP2B6 G516Tgenotype were included in the final model with population estimates for CL/F determined as 2.46, 4.60 and 7.33 L/h for the T/T, G/T and G/G genotype groups respectively. CONCLUSIONS: The inclusion of both age and weight to predict accurate EFV CL values for the respective genotype groups within this paediatric population was required, whereas the addition of gender and body surface area did not improve the predictions. The importance of introducing IOV in a PK model for a longitudinal study with sparsely collected data was again highlighted by this investigation.

Population pharmacokinetics of phenytoin in South African black patients.

In the routine care of 37 patients at the epilepsy outpatient clinic of Baragwanath Hospital, Johannesburg, 100 steady-state serum phenytoin concentrations were measured. Total and free phenytoin as well as albumin serum concentrations were determined. Computer analysed data were fitted to the Michaelis-Menten model for steady-state serum concentrations. As a function of the Michaelis-Menten constant (P less than 0.1) total serum phenytoin concentration provided a significantly better fit than free phenytoin combined with albumin serum concentrations. The Vm and Km of 6.5 mg/kg/d and 13.6 mumol/l respectively, determined by using total serum concentration, could be to estimate phenytoin dosage requirements in a hospital population.

Therapeutic drug level monitoring in the management of epilepsy.

A selected group of poorly controlled epileptic patients had their drug plasma concentrations measured. Of those on a single drug, 33% were noncompliant, 33% had drug concentrations in the subtherapeutic or toxic ranges and 34% had levels in the therapeutic range, 86% of which were in the low therapeutic range. In only 9% of the group on multiple drugs were both drug levels in the therapeutic range. Twenty-two per cent of patients were non-compliant for both drugs. Patients were followed up over 12 months with drug level monitoring and dosage adjustments; 49% were seizure-free and 36% had a reduction in seizure frequency of at least 50% over an 8-month period. All but 3.9% were put on a single-drug regimen, and 15.6%, which matched well with the number of non-compliant patients, had no change in seizure frequency. Therapeutic drug level monitoring is a most useful aid in rationalising drug therapy and improving seizure control.

Absorption properties of two theophylline sustained-release products in smokers.

The absorption of theophylline from two commercial products labelled as having sustained-release properties (Theo-dur; Rio-Ethicals; and Euphyllin Retard; Byk-Gulden) was compared with that of a solution of theophylline (Alcophyllin syrup; Propan-Lipworth) in a multiple-dose study in smokers. As regards bioavailability, results for Theo-dur and Euphyllin Retard tables were statistically indistinguishable from that for the standard, but both products showed significantly slower absorption as reflected by longer times to attain peak concentration and lower peak concentrations. Theo-dur exhibits better sustained-release properties than Euphyllin Retard as judged from the peak/trough ratio and the persistence of concentrations from 6 hours to 12 hours after administration. Assuming linear pharmacokinetics and projecting to therapeutic doses, Euphyllin Retard results in much wider fluctuations between peak and trough concentrations (18,9 and 9,8 micrograms/ml) than does Theo-dur (13,8 and 10,2 micrograms/ml), and this product might be more acceptable in smokers if given in an 8-hourly schedule.