Immunosuppressant Pharmacokinetics and Dosing Modifications in HIV-1 Infected Liver and Kidney Transplant Recipients

Abstract

Solid organ transplantation in human immunodeficiency virus (HIV)-infected individuals requiring con) is complicated by significant drug interactions. To assist in appropriate clinical management, we describe the pharmacokinetics and dosing modifications in 35 patients (20 kidney, 13 liver and two kidney-liver HIV-infected subjects with end-stage kidney or liver disease), on both IS and NNRTIs, PIs, and combined NNRTIs + PIs, in studies done at weeks 2-4 and/or 12 weeks after transplantation or after a change in IS or ARV drug regimen (n = 97 studies). CsA, SrL and FK concentrations were measured in whole blood by LC/MS. HIV-infected transplant recipients using PIs with IS had marked increases in CsA, FK or SrL trough levels compared to those on NNRTIs alone or to patients not on ARVs, necessitating either a reduction in dose or an increase in dosing interval. Subjects on efavirenz (EFV) and CsA required much higher doses of CsA than those using any other ARV. Changes in antiretroviral therapy should be carefully managed to avoid insufficient immunosuppression or toxicity due to drug interactions.

Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus

“…25 For example, addition of lopinavir/ritonavir (n ¼ 7 patients) reduced tacrolimus dose by 99% to maintain tacrolimus concentrations within the therapeutic range. 26 Similarly, during coadministration of Highly Active Antiretroviral Therapy (HAART) regimens with ritonavir-boosted HIV protease inhibitors, daily cyclosporine doses were reduced by 80%-95% to maintain cyclosporine exposure at pre-HAART levels.…”

Liver transplantation in human immunodeficiency virus-positive patients

“…NNRTIs (eg, efavirenz) are inducers of cytochrome P450 and lead to decreased levels of CNIs; PIs (eg, ritonavir/lopinavir) are inhibitors and, therefore, lead to increased levels of CNIs. 55 In our experience, tacrolimus doses as low as 1 mg/week have been required in individual cases. The use of raltegravir, a novel HIV-1 integrase inhibitor, in combination with nucleoside reverse-transcriptase inhibitors has been reported for 8 LT patients, who required only standard CNI dosing.…”

Update on kidney transplantation in human immunodeficiency virus infected recipients

“…Stopping NNRTIs may result in CNI toxicity [44] . Maraviroc, is a P-450 3A4 substrate, but does not inhibit or induce the enzyme and hence, it is not expected to interact with CNIs.…”