Lack of effect of efavirenz on the pharmacokinetics of tipranavir-ritonavir in healthy volunteers.

Previously it has been shown that tipranavir-ritonavir (TPV/r) does not affect efavirenz (EFV) plasma concentrations. This study investigates the effect of steady-state EFV on steady-state TPV/r pharmacokinetics. This was a single-center, open-label, multiple-dose study of healthy adult female and male volunteers. TPV/r 500/200 mg twice a day (BID) was given with food for 24 days. After dosing with TPV/r for 10 days, EFV 600 mg once a day was added to the regimen. Intensive pharmacokinetic (PK) sampling was done on days 10 and 24. Validated bioanalytical high-pressure liquid chromatography-tandem mass spectrometry methods were used to determine plasma tipranavir (TPV), ritonavir (RTV), and EFV concentrations. Thirty-four subjects were entered into the study, and 16 subjects completed it. The geometric mean ratios (90% confidence intervals) for TPV and RTV area under the curves, C(max)s, and C(min)s comparing TPV/r alone and in combination with EFV were 0.97 (0.87 to 1.09), 0.92 (0.81 to 1.03), and 1.19 (0.93 to 1.54) for TPV and 1.03 (0.78 to 1.38), 0.92 (0.65 to 1.30), and 1.04 (0.72 to 1.48) for RTV. Frequently observed adverse events were diarrhea, headache, dizziness, abnormal dreams, and rash. EFV had no effect on the steady-state PK of TPV or RTV, with the exception of a 19% increase in the TPV C(min), which is not clinically relevant. TPV/r can be safely coadministered with EFV and without the need for a dose adjustment.

Differential effects of tipranavir plus ritonavir on atorvastatin or rosuvastatin pharmacokinetics in healthy volunteers.

To identify pharmacokinetic (PK) drug-drug interactions between tipranavir-ritonavir (TPV/r) and rosuvastatin and atorvastatin, we conducted two prospective, open-label, single-arm, two-period studies. The geometric mean (GM) ratio was 1.37 (90% confidence interval [CI], 1.15 to 1.62) for the area under the concentration-time curve (AUC) for rosuvastatin and 2.23 (90% CI, 1.83 to 2.72) for the maximum concentration of drug in serum (Cmax) for rosuvastatin with TPV/r at steady state versus alone. The GM ratio was 9.36 (90% CI, 8.02 to 10.94) for the AUC of atorvastatin and 8.61 (90% CI, 7.25 to 10.21) for the Cmax of atorvastatin with TPV/r at steady state versus alone. Tipranavir PK parameters were not affected by single-dose rosuvastatin or atorvastatin. Mild gastrointestinal intolerance, headache, and mild reversible liver enzyme elevations (grade 1 and 2) were the most commonly reported adverse drug reactions. Based on these interactions, we recommend low initial doses of rosuvastatin (5 mg) and atorvastatin (10 mg), with careful clinical monitoring of rosuvastatin- or atorvastatin-related adverse events when combined with TPV/r.

Age-dependent pharmacokinetics of lamivudine in HIV-infected children.

The recommended dose of lamivudine in children is higher when compared with adults: 4 mg/kg vs approximately 2 mg/kg (150 mg) and administered twice a day. Limited data are available to demonstrate that this increased dose results in adequate exposure to lamivudine in children with human immunodeficiency virus (HIV) infection. Data were selected from children who were using lamivudine for at least 2 weeks before a full pharmacokinetic (PK) study was conducted. Lamivudine PK parameters were significantly related to age. The age of 6 years appeared to be a cutoff for a change in PK parameters of lamivudine, with children <6 years of age (n=17) having a median area under the curve 43% lower and a median peak plasma concentration 47% lower (both P<0.001) than older children (n=34). In conclusion, further investigation of the relationship between decreased lamivudine exposure and treatment outcome and long-term resistance development in younger children with HIV infection is warranted.

The effect of ABCB1 polymorphism on the pharmacokinetics of saquinavir alone and in combination with ritonavir.

This genotype panel study investigated the effect of ABCB1 polymorphism in exon 26 (C3435T), exon 21 (G2677T/A), and exon 12 (C1236T) on saquinavir pharmacokinetics and on the expression and activity of P-glycoprotein (P-gp) in peripheral blood monocytic cells (PBMCs). One hundred and fifty healthy volunteers were genotyped to identify 15 TT3435 and 15 CC3435 individuals. In these individuals, saquinavir pharmacokinetics were assessed after administration of a single oral dose of saquinavir 1,000 mg and saquinavir/ritonavir 1,000/100 mg. PBMC P-gp expression and activity were assessed in 15 and 19 subjects. The co-administration of ritonavir on study day 2 caused a significant increase in saquinavir exposure, in both TT3435 and CC3435 individuals. No correlation was observed between the ABCB1 C3435T, G2677T/A, and C1236T polymorphisms, separately and in haplotypes, with saquinavir pharmacokinetics, administered with or without ritonavir and with PBMC P-gp expression and activity. In conclusion, ABCB1 polymorphism has no pronounced effect on saquinavir exposure.

Effect of efavirenz treatment on the pharmacokinetics of nelfinavir boosted by ritonavir in healthy volunteers.

AIMS: A once-daily (q.d.) nucleoside-sparing regimen can prevent mitochondrial toxicity, overcome viral resistance and improve compliance. In the present study the effect of efavirenz on the pharmacokinetics and tolerability of once-daily nelfinavir/ritonavir was evaluated in healthy subjects. METHODS: This was a multiple-dose, open-label, single-group, two-period study in 24 healthy subjects. Each received from days 1-10 (period 1): 1875 mg nelfinavir plus 200 mg ritonavir q.d. with a 300-kcal snack. During days 11-20 (period 2) efavirenz 600 mg q.d. was added to the regimen. Blood samples were collected up to 24 h after dosing on days 10 (period 1) and 20 (period 2). High-performance liquid chromatography methods were used for the determination of the concentrations of all compounds. The main pharmacokinetic parameters were calculated using noncompartmental methods. RESULTS: All subjects completed the study. After the first period mean nelfinavir AUC(0-24 h), C(max) and C(24) were 49.6 mg h(-1) l(-1), 5.0 mg l(-1) and 0.37 mg l(-1), and the sum of nelfinavir plus its active metabolite M8 C(24) was 0.83 mg l(-1). The relative bioavailability, expressed as a geometric mean ratio (90% confidence interval) for nelfinavir AUC(0-24 h), C(max) and C(24) of period 2 compared with period 1 was: 1.30 (1.21, 1.40), 1.29 (1.19, 1.40) and 1.48 (1.32, 1.66). The sum of nelfinavir and M8 C(24) in period 2 was 0.99 mg l(-1), an increase of 19%. No serious adverse events occurred. CONCLUSIONS: The studied regimens were well tolerated. Nelfinavir/ritonavir given together with efavirenz resulted in a 48% higher mean C(24) concentration for nelfinavir, and the sum of nelfinavir and M8 C(24) concentrations was 0.99 mg l(-1). Efavirenz exposure in this study was similar to that reported previously, and therefore can be used effectively in combination with ritonavir and nelfinavir.

Pharmacokinetics of adjusted-dose lopinavir-ritonavir combined with rifampin in healthy volunteers.

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. Adjusted-dose regimens of lopinavir-ritonavir in combination with therapeutic drug monitoring and monitoring of liver function may allow concomitant use of rifampin.

Development and validation of transient isotachophoretic capillary zone electrophoresis for determination of peptides.

Although capillary zone electrophoresis (CZE) is known for its high resolution power and low mass detection limits, the concentration detection limits are rather poor when ultraviolet absorbance detection is used. To overcome this limitation, several on-column transient isotachophoresis (tITP) protocols have been developed and validated for the determination of both cationic and anionic model peptides, separately. Using this preconcentration method, up to 72% of the capillary can be filled with sample solution, without any loss in resolution. Thus, without any modification of the hardware set-up, the sensitivity is increased about two orders of magnitude. For the model cationic peptides (gonadorelin, angiotensin II) good linearity and reproducibility is observed in the 20 to 100 ng/mL concentration range. For the anionic peptides (N-t-Boc-Pentagastrin and two related peptides), a tITP method was developed using a dynamically coated capillary. The coating was prepared by adding Fluorad FC-135 to the leading electrolyte buffer. In this way a positively charged bilayer was formed on the inside of the capillary, producing an electroosmotic flow towards the outlet using reversed polarity conditions. In this way, acceptable analysis times were achieved. Using the developed tITP method, up to 72% of the capillary can be filled with sample solution as well. The anionic peptides are separated even better than when using CZE conditions. Linearity and reproducibility in the 20-100 ng/mL range proved to be excellent.