Coadministration of lopinavir-ritonavir, an antiretroviral protease inhibitor, at the standard dose (400/100 mg twice a day [BID]) with the antituberculous agent rifampin is contraindicated because of a significant pharmacokinetic interaction due to induction of cytochrome P450 3A by rifampin. In the present study, two adjusted-dose regimens of lopinavir-ritonavir were tested in combination with rifampin. Thirty-two healthy subjects participated in a randomized, two-arm, open-label, multiple-dose, within-subject controlled study. All subjects were treated with lopinavir-ritonavir at 400/100 mg BID from days 1 to 15. From days 16 to 24, the subjects in arm 1 received lopinavir-ritonavir at 800/200 mg BID in a dose titration, and the subjects in arm 2 received lopinavir-ritonavir at 400/400 mg BID in a dose titration. Rifampin was given at 600 mg once daily to all subjects from days 11 to 24. The multiple-dose pharmacokinetics of lopinavir, ritonavir, and rifampin were assessed. Twelve of 32 subjects withdrew from the study. For nine subjects lopinavir-ritonavir combined with rifampin resulted in liver enzyme level elevations. Pharmacokinetic data for 19 subjects were evaluable. Geometric mean ratios for the lopinavir minimum concentration in serum and the maximum concentration in serum (C max ) on day 24 versus that on day 10 were 0.43 (90% confidence interval [CI], 0.19 to 0.96) and 1.02 (90% CI, 0.85 to 1.23), respectively, for arm 1 (n ‫؍‬ 10) and 1.03 (90% CI, 0.68 to 1.56) and 0.93 (90% CI, 0.81 to 1.07), respectively, for arm 2 (n ‫؍‬ 9). Ritonavir exposure increased from days 10 to 24 in both arms. The geometric mean C max of rifampin was 13.5 mg/liter (day 24) and was similar between the two arms. Adjusteddose regimens of lopinavir-ritonavir in combination with therapeutic drug monitoring and monitoring of liver function may allow concomitant use of rifampin.

Nelfinavir is the only currently licensed HIV-protease inhibitor that has an active metabolite present in potentially therapeutic concentrations. This metabolite, nelfinavir hydroxyl-t-butylamide (also known as M8 or AG1402), is the product of enzymatic conversion of nelfinavir by cytochrome P450 2C19 ( CYP2C19 ) [1]. Previous studies have demonstrated that inherited (the homozygote's CYP2C19 * 2 allele) and acquired (severe liver disease) deficiency of CYP2C19 result in diminished formation of M8 [2,3].However, the frequency of heterozygote mutants of CYP2C19 * 2 (G681A mutation) in the general caucasian population is far greater than that of homozygote mutants (15% vs. 2%) [4,5]. If these heterozygotes differed with respect to nelfinavir pharmacokinetics, the CYP2C19 * 2 polymorphism would affect many more patients, and thus may have greater clinical relevance.Data for this analysis were selected from 24 healthy subjects who participated in a study on the effect of food on the pharmacokinetics of nelfinavir. Prior to enrolment, subjects were screened for the CYP2C19 polymorphism by polymerase chain reaction. Subjects who were homozygotes for any of the variant alleles of CYP2C19 (either *2, *3, *4 or *5) were excluded from the trial. Of the 36 subjects screened, one subject was a homozygous carrier of the CYP2C19 * 2 mutation and, of the 24 subjects included, eight were heterozygotes. No CYP2C19 *3, *4 or *5 mutants were found. The pharmacokinetics of nelfinavir and M8 were characterized by noncompartmental methods following a 1250-mg dose taken with a standardized breakfast (containing about 737 kCal, 28 g of fat). At that time of the study, subjects had been taking nelfinavir 1250 mg twice daily for at least 10 days. None of the subjects was taking concurrent medications that are potential inhibitors of CYP2C19 . Nelfinavir and M8 plasma concentrations were determined by a validated high-performance liquid chromatography assay with a lower limit of quantification for both agents of 0.04 mg l − 1 [6]. A nelfinavir + M8 concentration at 12 h after dosing ( C 12 h ) that was below 1.0 mg l − 1 was defined as subtherapeutic based on previous studies in HIV-infected patients [7,8].Overall, the median ratio of the AUC of M8 and nelfinavir was 0.34 with an interquartile range of 0.27-0.39. Minimum and maximum values were 0.10 and 0.50, respectively. These figures are consistent with previous reports in HIV-infected patients. No association was observed between the M8/nelfinavir AUC ratio and either gender, age (median age 40 years; range 22-63 years) or smoking habits (six smokers; maximum of 10 cigarettes per day) ( t -test: all P -values were > 0.51). In contrast, there was a significant difference in the M8/ nelfinavir AUC ratios between CYP2C19 wt/wt subjects and CYP2C19 *2/wt subjects {mean difference [95% confidence interval (CI)] 0.14 (0.07, 0.21); P < 0.001} (Figure 1). However, the oral clearance of nelfinavir was not significantly different between the two genotypes [mean difference (95% CI) 9.1 l h − 1 (...

Unboosted fosamprenavir should not be used concomitantly with posaconazole.

Large differences in pharmacokinetic parameters can be excluded for Lopimune paediatric tablets when compared with the branded product and taken on an empty stomach, and also for Lopimune granules when these are taken with food.

ObjectivesTo evaluate the use of raltegravir with unboosted atazanavir in combination with one nucleoside reverse transcriptase inhibitor (NRTI) (lamivudine or emtricitabine) as a potentially well-tolerated once-daily (qd) maintenance regimen. MethodsWe compared the pharmacokinetics of raltegravir 400 mg twice daily (bid) with raltegravir 800 mg qd in HIV-infected patients (n = 17) on unboosted atazanavir (600 mg qd) in combination with lamivudine or emtricitabine. ResultsThe area under the plasma concentration vs. time curve for a dose interval t (AUC0-t) of 800 mg qd divided by 2 was not significantly different from the AUC0-t of 400 mg bid (P = 0.664) but the minimum concentration (Cmin) was 72% lower with the qd regimen (P = 0.002). The regimen was well tolerated and the viral load remained undetectable in all patients during the 6 weeks of the study follow-up. ConclusionsA qd regimen of raltegravir 800 mg, atazanavir 600 mg and lamivudine or emtricitabine resulted in favourable pharmacokinetic profiles and good short-term safety and efficacy data. Larger phase IIb studies are needed to explore this novel regimen.