Objective We evaluated the pharmacokinetics (pk) of raltegravir in HIV-infected women during pregnancy and postpartum. Methods IMPAACT 1026s is an on-going prospective study of antiretroviral pk during pregnancy (NCT00042289). Women receiving 400 mg raltegravir twice daily in combination antiretroviral therapy had intensive steady state 12-hour pk profiles performed during pregnancy and at 6–12 weeks postpartum. Targets were trough concentration above 0.035 µg/mL, the estimated tenth percentile in non-pregnant historical controls. Results Median raltegravir AUC was 6.6 µg*hr/mL for second trimester (n= 16), 5.4 µg*hr/mL for third trimester (n=41), and 11.6 µg*hr/mL postpartum (n= 38) (p=0.03 pp vs 2nd trimester, p=0.001 pp vs third trimester). Trough concentrations were above the target in 69%, 80%, and 79% of second trimester, third trimester and postpartum subjects respectively, with wide variability (<0.010–0.917 µg/mL), and no significant difference between third trimester and postpartum trough concentrations was detected. The median ratio of cord blood/maternal raltegravir concentrations was 1.5. HIV RNA levels were < 400 copies/mL in 92% of women at delivery. Adverse events included elevated liver transaminases in one woman and vomiting in one. All infants with known status are HIV-uninfected. Conclusions Median raltegravir AUC was reduced by approximately 50% during pregnancy; trough concentrations were frequently below target both during late pregnancy and postpartum. Raltegravir readily crossed the placenta. High rates of viral suppression at delivery and the lack of a clear relationship between raltegravir concentration and virologic effect in nonpregnant adults suggest that despite the decreased exposure during pregnancy, a higher dose is not necessary.
Background Drug-drug interactions complicate management of co-infection with HIV-1 and Mycobacterium tuberculosis. Bedaquiline (formerly TMC207), an investigational agent for the treatment of tuberculosis, is metabolized by cytochrome P450 (CYP) 3A which may be induced by the antiretroviral drug efavirenz. Methods This was a Phase I pharmacokinetic drug interaction trial. Each healthy volunteer received two 400 mg doses of bedaquiline, the first alone, and the second with concomitant steady-state efavirenz. Plasma pharmacokinetic sampling for bedaquiline and its N-monodesmethyl metabolite (M2) was performed over 14 days after each bedaquiline dose. Steady-state efavirenz pharmacokinetics were also determined. Efavirenz metabolizer status was based on CYP2B6 composite 516/983 genotype. Results Thirty-three of 37 enrolled subjects completed the study. Geometric mean ratios (GMR) for bedaquiline with efavirenz versus bedaquiline alone were 0.82 (90% CI 0.75 to 0.89) for the 14-day area under the concentration-time curve (AUC0-336h) and 1.00 (90% CI 0.88 to 1.13) for the maximum concentration (Cmax). For M2, the GMR was 1.07 (90% CI 0.97 to 1.19) for AUC0-336h and 1.89 (90% CI 1.66 to 2.15) for Cmax. There were no Grade 3 or 4 clinical adverse events. One subject developed asymptomatic Grade 3 serum transaminase elevation, prompting study drug discontinuation. Efavirenz concentrations stratified by CYP2B6 genotype were similar to historical data. Conclusions Single-dose bedaquiline was well-tolerated alone and with steady-state efavirenz. The effect of efavirenz on bedaquiline concentrations is unlikely to be clinically significant.
Despite a statistically significant decrease in C(max) of IDV in the marijuana arm, the magnitude of changes in IDV and NFV pharmacokinetic parameters in the marijuana arm are likely to have no short-term clinical consequence. The use of marijuana or dronabinol is unlikely to impact antiretroviral efficacy.
Piperaquine (PQ) is part of a first-line treatment regimen for Plasmodium falciparum malaria recommended by the World Health Organization (WHO). We aimed to determine the major metabolic pathway(s) of PQ in vitro. A reliable, validated tandem mass spectrometry method was developed. Concentrations of PQ were measured after incubation with both human liver microsomes (HLMs) and expressed cytochrome P450 enzymes (P450s). In pooled HLMs, incubations with an initial PQ concentration of 0.3 µM resulted in a 34.8 ± 4.9% loss of substrate over 60 min, corresponding to a turnover rate of 0.009 min−1 (r2 = 0.9223). Miconazole, at nonspecific P450 inhibitory concentrations, resulted in almost complete inhibition of PQ metabolism. The greatest inhibition was demonstrated with selective CYP3A4 (100%) and CYP2C8 (66%) inhibitors. Using a mixture of recombinant P450 enzymes, turnover for PQ metabolism was estimated as 0.0099 min−1; recombinant CYP3A4 had a higher metabolic rate (0.017 min−1) than recombinant CYP2C8 (p < .0001). Inhibition of CYP3A4-mediated PQ loss was greatest using the selective inhibitor ketoconazole (9.1 ± 3.5% loss with ketoconazole vs 60.7 ± 5.9% with no inhibitor, p < .0001). In summary, the extent of inhibition of in vitro metabolism with ketoconazole (83%) denotes that PQ appears to be primarily catalyzed by CYP3A4. Further studies to support these findings through the identification and characterization of PQ metabolites are planned.
Nelfinavir does not appreciably penetrate into the CSF. The clinical importance of this observation is not certain, in that in four study subjects who initiated nelfinavir in combination with other antiretroviral therapy, a comparable degree of viral suppression was obtained in both the CSF and the blood when sampled 4 weeks or later after initiating therapy.
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