Effect of coadministered lopinavir and ritonavir (Kaletra) on tacrolimus blood concentration in liver transplantation patients

Abstract

With the advent of highly active antiretroviral therapy (HAART), HIV positivity is no longer a contraindication for liver transplantation. Some of the antiretroviral agents, particularly protease inhibitors (e.g., ritonavir, indinavir, and nelfinavir) have been described as potent inhibitors of the metabolism of certain immunosuppressive drugs. In this article we describe a profound interaction between tacrolimus and Kaletra (Abbott Laboratories, Chicago, IL) (a combination of lopinavir and ritonavir) in 3 liver transplantation patients. Patient 1, who was maintained on a 5 mg twice daily dose of tacrolimus with a trough blood concentration around 10.6 ng/mL, required only 0.5 mg of tacrolimus per week after addition of Kaletra to achieve similar tacrolimus blood concentrations, with a half-life of 10.6 days. In patient 2, the area under the blood concentration versus time curve for tacrolimus increased from 31 ng/mL/h to 301 ng/mL/h after addition of Kaletra, with a corresponding half-life of 20 days. When the patient was subsequently switched to nelfinavir, the half-life decreased to 10.3 days. Patient 3, who was maintained with 4 to 8 mg/d of tacrolimus and a corresponding blood concentration of 10 ng/mL before Kaletra, required a tacrolimus dose of 1 mg/wk and tacrolimus concentrations of 5 ng/mL with Kaletra. In conclusion, a combination of lopinavir and ritonavir led to a much more profound increase in tacrolimus blood concentrations than use of single protease inhibitor, nelfinavir. A tacrolimus dose of less than 1 mg/wk may be sufficient to maintain adequate blood tacrolimus concentrations in patients on Kaletra. Patients may not need a further dose of tacrolimus for 3 to 5 weeks depending on liver function when therapy with Kaletra is initiated. Great caution is required in the management of tacrolimus dosage when Kaletra is introduced or withdrawn in HIV-positive patients after liver transplantation, particularly in the presence of hepatic dysfunction. (Liver Transpl 2003;9:954-960.)

Combination Drug Products for HIV–A Word of Caution for the Transplant Clinician

“…This resulted in a dosing frequency of 0.5 mg twice per week or approximately 98% reduction of the usual dose. The dosing administration was similar to that seen in ritonavir-treated kidney and liver recipients, in which dose reductions of up to 99% have been reported (13)(14)(15). This finding is also consistent with pharmacokinetic data demonstrating similar inhibition of midazolam (a CYP3A substrate) clearance when compared to ritonavir (16).…”

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

“…Tacrolimus (1,3,5,7) and CsA (1,2,4,6) have been previously reported to require dosing adjustments in both liver and kidney HIV-infected transplant patients. We report here on 97 pharmacokinetic studies conducted in 35 HIV-infected subjects at 2 and 12 weeks after kidney or liver transplantation.…”

Drug–Drug Interactions Between Antiretroviral and Immunosuppressive Agents in HIV-Infected Patients After Solid Organ Transplantation: A Review

“…36,38,[42][43][44][45][46][47][48][49][50] Moreover, in patients on RTV-boosted PIs even higher drastic dosage reductions up to 120-fold are necessary to achieve therapeutic through levels of tacrolimus, cyclosporine, and sirolimus. 7,35,37,38,42,45,47,[51][52][53][54][55][56][57][58][59][60][61][62][63][64] Initiation of a posttransplant CNI dosing strategy similar to that used in a non-HIV positive patient can immediate lead to extremely high persistent CNI inhibitor levels and concurrent (nephro)toxicity [59]. CNI half life is prolonged 5-to 20-fold because of the systemic inhibition of CYP 3A and Pgp, resulting in dosing regimens of 0.5-1 mg once weekly for tacrolimus and 25 mg every 1-2 days for cyclosporine in kidney and liver transplant recipients.…”

“…The management of cART and immunosuppressive therapy is extremely challenging, as witnessed by high allograft rejection rates observed in this immune system dysregulated population, 5 but also increased risk of infections, high rates of drug toxicity and the profound drug-drug interactions between cART and immunosuppressants. [6][7][8] As transplantation in the HIV population becomes increasingly common there is a need to optimize the pharmacologic management of this population. Specifically, there is a need for cART regimens that have less potential for drug-drug interactions and minimal overlapping toxicities when used in combination with common immutnosuppressive regimens.…”