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The drug-drug interaction between rifabutin (RFB) and darunavir/ritonavir (DRV/r) was examined in a randomized, three-way crossover study of HIV-negative healthy volunteers who received DRV/r 600/100 mg twice a day (BID) (treatment A), RFB 300 mg once a day (QD) (treatment B), and DRV/r 600/100 mg BID plus RFB 150 mg every other day (QOD) (treatment C). The sequence of treatments was randomized, and each treatment period lasted 12 days. Full pharmacokinetic profiles were determined for DRV, ritonavir, and RFB and its active metabolite, 25- O -desacetylrifabutin (desRFB), on day 13. The DRV and ritonavir areas under the plasma concentration-time curve from zero to 12 h (AUC 12h ) increased by 57% and 66%, respectively, in the presence of RFB. The RFB exposure was comparable between treatment with RFB QD alone (treatment B) and treatment with DRV/r plus RFB QOD (treatment C); however, based on least-square means ratios, the minimum plasma concentration ( C min ) increased by 64% and the maximum plasma concentration ( C max ) decreased by 28%, respectively. The exposure (AUC within the dosage interval and at steady state [AUC τ ]) to desRFB was considerably increased (by 881%) following treatment with DRV/r/RFB. The exposure to the parent drug plus the metabolite increased 1.6-fold in the presence of DRV/r. Adverse events (AEs) were more commonly reported during combined treatment (83% versus 44% for RFB and 28% for DRV/r); similarly, grade 3-4 AEs occurred in 17% versus 11% and 0%, respectively, of volunteers. Eighteen of 27 volunteers (66.7%) prematurely discontinued the trial; all volunteers discontinuing for safety reasons ( n = 9) did so during RFB treatment phases. These results suggest that DRV/r may be coadministered with RFB with a dose adjustment of RFB to 150 mg QOD and increased monitoring for RFB-related AEs. Based on the overall safety profile of DRV/r, no dose adjustment of DRV/r is considered to be warranted. Given the safety profile seen with the combination of RFB with a boosted protease inhibitor in this and other studies, it is not recommended to conduct further studies with this combination in healthy volunteers.

Etravirine, a next-generation nonnucleoside reverse transcriptase inhibitor, and raltegravir, an integrase strand transfer inhibitor, have separately demonstrated potent activity in treatment-experienced, human immunodeficiency virus (HIV)-infected patients. An open-label, sequential, three-period study with healthy, HIV-seronegative subjects was conducted to assess the two-way interaction between etravirine and raltegravir for potential coadministration to HIV-infected patients. In period 1, 19 subjects were administered 400 mg raltegravir every 12 h (q12 h) for 4 days, followed by a 4-day washout; in period 2, subjects were administered 200 mg etravirine q12 h for 8 days; and in period 3, subjects were coadministered 400 mg raltegravir and 200 mg etravirine q12 h for 4 days. There was no washout between periods 2 and 3. Doses were administered with a moderate-fat meal. Etravirine had only modest effects on the pharmacokinetics of raltegravir, while raltegravir had no clinically meaningful effect on the pharmacokinetics of etravirine. For raltegravir coadministered with etravirine relative to raltegravir alone, the geometric mean ratio (GMR) and 90% confidence interval (CI) were 0.90 and 0.68 to 1.18, respectively, for the area under the concentration curve from 0 to 12 h (AUC0-12), 0.89 and 0.68 to 1.15, respectively, for the maximum concentration of drug in serum (Cmax), and 0.66 and 0.34 to 1.26, respectively, for the trough drug concentration (C12); the GMR (90% CI) for etravirine coadministered with raltegravir relative to etravirine alone was 1.10 (1.03, 1.16) for AUC0-12, 1.04 (0.97, 1.12) forCmax, and 1.17 (1.10, 1.26) forC12. All drug-related adverse clinical experiences were mild and generally transient in nature. No grade 3 or 4 adverse experiences or discontinuations due to adverse experiences occurred. Coadministration of etravirine and raltegravir was generally well tolerated; the data suggest that no dose adjustment for either drug is necessary.

We evaluated the pharmacokinetics of stavudine (d4T) and didanosine (ddI) in neonates. Eight neonates born to human immunodeficiency virus-infected mothers were enrolled to receive 1 mg of d4T per kg of body weight twice daily and 100 mg of ddI per m 2 once daily in combination with nelfinavir for 4 weeks after birth. Pharmacokinetic evaluations were performed at 14 and 28 days of age. For d4T, on days 14 and 28, the median areas under the concentration-time curves from 0 to 12 h (AUC 0–12 s) were 1,866 and 1,603, ng · h/ml, respectively, and the median peak concentrations ( C max s) were 463 and 507 ng/ml, respectively. For ddI, on days 14 and 28, the median AUC 0–10 s were 1,573 and 1,562 h · ng/ml, respectively, and the median C max s were 627 and 687 ng/ml, respectively. Systemic levels of exposure to d4T were comparable to those seen in children, suggesting that the pediatric dose of 1 mg/kg twice daily is appropriate for neonates at 2 to 4 weeks of age. Levels of exposure to ddI were modestly higher than those seen in children. Whether this observation warrants a reduction of the ddI dose in neonates is unclear.

Limited data are available on antiretroviral drug concentrations in seminal plasma during a dosing interval. Further, since human ejaculate is composed of fluids originating from the testes, the seminal vesicles, and the prostate, all having different physiological characteristics, drug concentrations in total seminal plasma do not necessarily reflect concentrations in the separate compartments. Five human immunodeficiency virus type 1-infected patients on nevirapine (NVP; 200 mg twice a day [b.i.d.]) and/or indinavir (IDV; 800 mg b.i.d. with ritonavir, 100 mg b.i.d.) regimens used a split ejaculate technique to separate seminal plasma in two fractions, representing fluids from the testes and prostate (first fraction) and fluids from the seminal vesicles (second fraction). Split-ejaculate samples were provided at 0, 2, 5, and 8 h after drug ingestion, on separate days after 3 days of sexual abstinence. NVP and IDV showed time-dependent concentrations in seminal plasma, with peak concentrations in both fractions at 2 and 2 to 5 h, respectively, after drug ingestion. The NVP concentrations were not significantly different between the first and second fractions of the ejaculate at all time points measured and were in the therapeutic range, except for the predose concentration in two patients. The median (range) predose IDV concentrations in the first and second fractions of the ejaculate were 448 (353 to 1,015) ng/ml and 527 (240 to 849) ng/ml, respectively (P= 0.7). In conclusion, NVP and IDV concentrations in seminal plasma are dependent on the time after drug ingestion. Furthermore, our data suggest that NVP and IDV achieve therapeutic concentrations in both the testes and prostate and the seminal vesicles throughout the dosing interval.

The effects of darunavir-ritonavir at 600 and 100 mg twice daily (b.i.d.) alone, 200 mg of etravirine b.i.d. alone, or 600 and 100 mg of darunavir-ritonavir b.i.d. with 200 mg etravirine b.i.d. at steady state on the steady-state pharmacokinetics of maraviroc, and vice versa, in healthy volunteers were investigated in two phase I, randomized, two-period crossover studies. Safety and tolerability were also assessed. Coadministration of 150 mg maraviroc b.i.d. with darunavir-ritonavir increased the area under the plasma concentration-time curve from 0 to 12 h (AUC 12 ) for maraviroc 4.05-fold relative to 150 mg of maraviroc b.i.d. alone. Coadministration of 300 mg maraviroc b.i.d. with etravirine decreased the maraviroc AUC 12 by 53% relative to 300 mg maraviroc b.i.d. alone. Coadministration of 150 mg maraviroc b.i.d. with etravirine-darunavir-ritonavir increased the maraviroc AUC 12 3.10-fold relative to 150 mg maraviroc b.i.d. alone. Maraviroc did not significantly affect the pharmacokinetics of etravirine, darunavir, or ritonavir. Short-term coadministration of maraviroc with darunavir-ritonavir, etravirine, or both was generally well tolerated, with no safety issues reported in either trial. Maraviroc can be coadministered with darunavir-ritonavir, etravirine, or etravirine-darunavir-ritonavir. Maraviroc should be dosed at 600 mg b.i.d. with etravirine in the absence of a potent inhibitor of cytochrome P450 3A (CYP3A) (i.e., a boosted protease inhibitor) or at 150 mg b.i.d. when coadministered with darunavir-ritonavir with or without etravirine.