12th Conference on Retroviruses and Opportunistic Infections (12th CROI)

McCance-Katz EF, Pade P, Friedland G, Morse G, Moody D, and Rainey P.

The purpose of this study was to examine the possible pharmacokinetic and pharmacodynamic effects of using buprenorphine in opioid-dependent individuals who are being treated with efavirenz.

10 opioid-dependent HIV-negative subjects who were on a stable dose of buprenorphine for a minimum of two weeks, had samples obtained over a 24 hour period to determine the pharmacokinetics of the drug. After which, subjects were administered efavirenz for 15 days and samples were again obtained to determine the pharmacokinetics of buprenorphine and efavirenz. Before and after efavirenz administration objective opiate withdrawal scores were documented.

The authors concluded that efavirenz administration was associated with a significant change in the pharmacokinetics of buprenorphine; this was in respect to a decrease in AUC, an increase in clearance, and a decrease in Cmax and Cmin. As well, buprenorphine showed a decrease in half-life of elimination from 26 hours to 18.5 hours. No opiate withdrawal syndromes were noted throughout the study, and efavirenz levels were maintained within the therapeutic range.

Although this pilot study was only conducted in 10 subjects, it provides positive preliminary findings about the substitution of buprenorphine for methadone when treating opioid-dependent patients who require concurrent treatment with efavirenz as part of their anti-retroviral therapy. This study suggests that although efavirenz significantly decreases buprenorphine concentrations in the blood, it will not precipitate an opiate withdrawal syndrome when administered to patients concurrently treated with buprenorphine over 2 weeks as it does in patients concurrently treated with methadone. As well, the concurrent administration of buprenorphine does not decrease the levels of efavirenz below the therapeutic range.

Burger D, Agarwala S, Child M, Wang Y, Grasela D.

The purpose of this study was to assess the safety and pharmacokinetic profile of atazanavir (ATV) when given concurrently with ritonavir (RIT) and rifampin (RIF).

In this study, 71 healthy subjects were randomized to receive one of the following: 6 days of dosing with 400mg of Atazanavir (A), or 10 days of dosing with 300/100mg of ATV/RTV (B) for pharmacokinetic evaluation at the end of each specific cycle. Then subjects received 300/100mg (C), 300/200mg (D), or 400/200mg of ATV/RIT (E), all with 600mg of rifampin. Steady state pharmacokinetic evaluation was completed after 10 days for all three of these drugs and desacetyl-RIF.

The results were noted as follows: ATV AUC values were comparable, but Cmin (GMR = 0.40) was lower for treatment E than for ATV alone. There was a substantial reduction in ATV exposure in C and D compared to A or B and to E compared to B. Geometric mean ratios (90% CI) for ATV AUC in treatment (C), (D), and (E) compared to (A) were 0.43 (0.37,0.49), 0.69 (0.62, 0.78), and 1.10 (0.90, 1.35), respectively. In all regimens RIF and desacetyl-RIF was ~1.6 and 2.5x higher than with RIF alone in the safety arm. One subject in treatment (D) and (E) experienced grade ¾ ALT/AST.

The authors concluded that this combination resulted in inadequate ATV plasma concentrations and there was a need to investigate other dosing combinations.

Teicher E, Taburet A, Vincent I, Faivre L, Abbara C, Samuel D, Duclos-Vallee J, Vittecoq D.

The purpose of this study was to manage drug-drug interactions between tacrolimus and HAART.

This study was conducted in 10 HIV+ orthotopic liver transplant patients. All patients had their HAART stopped for 10 days after surgery. Patients received the immunosuppressive agent tacrolimus, whose blood concentration was targeted at 8-20ng/mL for the first 6 weeks, and 5-15ng/mL following week 6. As well, subjects were administered appropriate anti-infective prophylaxis, and prednisolone. Of the 10 subjects pharmacokinetic parameters were examined for 8 on two occasions at normalization of liver function (A) and 10 days after reinitiating their standard dosage of HAART (B).

Tacrolimus blood concentrations were maintained in the correct range and the viral load was <50 copies/mL for all subjects. The results were as follows: Tacrolimus half-life in hours from Cmax to Cmin, and oral clearance changed from 9.9 9.1, and 9.4 6.4, respectively in A to B in the patient reinstated on nucleoside analogs. 26.9 12.1 and 8.1 24.4 in half life, and 10.7 14.9 and 10.5 13.4 in oral clearance in 2 patients reinstated on efavirenz. 13.4 27.7 and 14.8 95.5 in half life, and 5.3 3.0 and 12.0 1.1 in oral clearance in 2 patients reinstated on nelfinavir. 6.3 120.7, 7.4 69.1, and 9.1 233.7 in half life, and 33.1 0.5, 19.4 0.4, and 15.6 0.9 in oral clearance in 3 patients reinstated on lopinavir/ritonavir.

The authors conclude that when nelfinavir and lopinavir/ritonavir are given concurrently with tacrolimus, the patient's tacrolimus dose should be decreased. However, more importantly they note that this is feasible to manage with therapeutic drug monitoring.

Adkinsin K, Shachoy-Clark A, Fang L, Lou Y, Otto V, Berrey M, Piscitelli S.

The purpose of this study was to evaluate in healthy subjects how lopinavir/ritonavir affected the steady-state pharmacokinetics of the spirodiketopiperazine CCR5 antagonist 873140, a known in vitro CYP450 3A substrate.

The first phase of this study was preformed to establish baseline pharmacokinetics and safety. 8 patients received a 50mg dose of 873140 with or without a 100mg dose of ritonavir. The second part of this study was preformed on 24 subjects and consisted of 3 periods. In the first period the subjects received 400mg of the experimental drug twice daily for 7 days. In the second period subjects were to receive 400/100mg of the lopinavir/ritonavir combination twice daily for 14 days, then in period three the subjects received both 873140 and lopinavir/ritonavir together at the same dosage for 7 days. Sampling was obtained on the last day in each period.

The investigators discovered that AUC and Cmax of the experimental drug was increased 2.1-2.3 fold by a single dose of ritonavir. In the second part of this study it was discovered that the CCR5 antagonist's AUC was increased by 7.7-fold, Cmax by 6.2-fold, and Cmin by 7.1-fold. The evaluation showed no change lopinavir pharmacokinetics and a small change in ritonavir AUC and Cmax. As well, adverse effects were minimal, mostly related to gastrointestinal complaints, and 2 of 24 subjects discontinued for reasons unrelated to study drug.

The authors concluded that Kaletra coadministration resulted in significant elevation in the 873140 drug concentration but that this combination of drugs was well tolerated.