Continually maintaining maximally suppressive drug concentrations represents a key defence against the emergence of resistance. If drug levels fall and replication occurs, the opportunity for mutant virus to be selected occurs. It has been increasingly recognized that variability in the pharmacokinetics of antiretrovirals, particularly protease inhibitors (PIs), means that drug exposure is not always optimal, giving the virus a chance to replicate. A significant number of patients receiving PIs two or three times daily will have trough (Ctrough or Cmin) plasma concentrations, which are close to, or below, the plasma protein binding-corrected inhibitory concentration (IC50 or IC95) during the dosing interval. It is primarily in this context that therapeutic drug monitoring of PIs has been proposed as an aid to patient management, to ensure that patients maintain adequate drug concentrations throughout the dosing interval. Ideally, an antiretroviral drug will have a pharmacokinetic (PK) profile that maintains drug levels well above the viral inhibitory concentration throughout the entire dosing interval. Beneficial drug-drug interactions have been shown to improve PI pharmacokinetics. Ritonavir (RTV) inhibits the key enzymes that limit the bioavailability or speed the metabolism of other PIs. It is therefore increasingly used for boosting and maintaining PI plasma concentrations. At low (100 mg twice a day) doses it acts as a pharmacoenhancer of indinavir (IDV), amprenavir, saquinavir, lopinavir and to a more limited degree nelfinavir. Using a pharmacoenhancer with a PI results in increased exposure to the PI, higher Cmin levels, and in most cases prolonged elimination half-lives. The long-term clinical benefits of PK enhancing are unknown as are the long-term toxicities, although the incidence of nephrolithiasis with IDV appears increased when IDV is combined with low-dose RTV in HIV-infected patients. Head-to-head clinical comparisons of boosted PI regimens will help answer some of the questions that remain with regard to PK enhancement.

Patients taking oral contraceptive steroids (OCS) are known to suffer contraceptive failure while taking anticonvulsants such as phenobarbitone, phenytoin and carbamazepine. We have studied the single dose kinetics of ethinyloestradiol (EE2); 50 ,ug, and levonorgestrel (Ng); 250 p,g in groups of women before and 8-12 weeks after starting therapy with phenytoin (n = 6) and carbamazepine (n = 4). The area under the plasma concentration-time curve (AUC) was measured over a 24 h period for each steroid and significant reductions were seen with both anticonvulsants. Phenytoin reduced the AUC for EE2 from 806 ± 50 (mean ± s.d.) to 411 ± 132 pg ml-' h (P < 0.05) and for Ng from 33.6 ± 7.8 to 19.5 ± 3.8 ng ml-' h (P < 0.05). Carbamazepine reduced the AUC for EE2 from 1163 ± 466 to 672 ± 211 pg ml-' h (P < 0.05) and for Ng from 22.9 ± 9.4 to 13.8 ± 5.8 ng ml-' h (P < 0.05). These changes are compatible with the known enzyme inducing effects of phenytoin and carbamazepine. Patients taking these anticonvulsants will need to be given increased doses of OCS (equivalent to 50-100 ,ug EE2 daily) to achieve adequate contraceptive effects.

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The aim of the study was to characterize the impact of the cytochrome P450 2B6 (CYP2B6), CYP3A4, CYP3A5 and ATP-binding cassette sub-family B member 1 (ABCB1) polymorphisms on nevirapine plasma concentrations. MethodsA total of 104 patients (82% male; 26% non-Caucasian) were genotyped for eight single nucleotide polymorphisms at four loci (CYP2B6, CYP3A4, CYP3A5 and MDR1). Nevirapine plasma concentrations were determined using high-performance liquid chromatography. ResultsNon-Caucasian ethnicity [5609 ng/mL (n 5 27) for non-Caucasians vs. 3771 ng/mL (n 5 77) for Caucasians; Po0.0001] and CYP2B6 516G ! T [GG, 3574 ng/mL (n 5 50); GT, 4634 ng/mL (n 5 50); TT, 8170 ng/mL (n 5 4); P analysis of variance (ANOVA) 5 0.001] were significantly associated with a higher nevirapine trough concentration (C trough ). The latter association was maintained with both 200 mg twice daily (bid) and 400 mg once daily (qd) dosing [GG, 3527 ng/mL (n 5 30); GT, 4525 ng/mL (n 5 32); TT, 7020 ng/mL (n 5 2); P ANOVA 5 0.05 and GG, 3645 ng/mL (n 5 20); GT, 4861 ng/mL (n 5 17); TT, 9508 ng/mL (n 5 2); P ANOVA 5 0.01, respectively]. In a multivariable analysis, CYP2B6 516G ! T and non-Caucasian ethnicity remained significant predictors of nevirapine C trough but CYP2B6 516G ! T homozygosity had the greatest effect (108% higher, 46% higher). No associations were found between nevirapine C trough and the remaining polymorphisms. ConclusionIn this population, both non-Caucasian ethnicity and carriage of the variant allele of CYP2B6 516G ! T were significant predictors of nevirapine C trough . The association between CYP2B6 516G ! T and higher plasma nevirapine exposure was maintained at both bid and qd dosing.Keywords: drug disposition, metabolism, pharmacogenetics, pharmacokinetics Accepted 18 November 2008 IntroductionNevirapine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) that is an alternative component of first-line antiretroviral regimens in HIV-infected individuals [1]. It is commonly prescribed in resource-poor settings for the treatment of HIV-1-infected children and adults and in the prevention of mother-to-child transmission (PMTCT) [2].The use of nevirapine is limited by a potentially fatal, immune-mediated hypersensitivity reaction which can manifest as hepatotoxicity, fever and/or rash [3,4] and a fragile genetic barrier to the development of drug resistance [5]. Higher plasma levels of nevirapine have been reported to be associated with improved virological response and reduced selection of resistant mutations [6][7][8]. There are conflicting reports on the association between nevirapine plasma levels and the development of adverse events [9][10][11].Previous studies have found ethnicity, gender, weight and underlying hepatic disease to be predictive of DOI: 10.1111/j.1468-1293.00689.x HIV Medicine (2009 r 2009 British HIV Association 310 nevirapine plasma concentrations [12][13][14]. Nevirapine is primarily metabolized by the cytochrome P450 3A4 (CYP3A4) and 2B6 (CYP2B6) enzymes into its major metabolites 2-hydr...

Primaquine showed mixed inhibition. Dixon plots confirmed the type of inhibition produced. 4 Although the competitive inhibition between some sulphonamides and tolbutamide is consistent with metabolism by the same isozyme of cytochrome P-450 it does not prove it and further studies with purified enzymes will be necessary to confirm this.