ritonavir and Hypokalemia

ModraDoc006 is a novel docetaxel tablet formulation that is co-administrated with the cytochrome P450 3A4 and P-glycoprotein inhibitor ritonavir (r): ModraDoc006/r.. This study evaluated the effect of food consumed prior to administration of ModraDoc006/r on the pharmacokinetics of docetaxel and ritonavir.. Patients with advanced solid tumours were enrolled in this randomized crossover study to receive ModraDoc006/r in a fasted state in week 1 and after a standardized high-fat meal in week 2 and vice versa. Pharmacokinetic sampling was conducted until 48 h after both study drug administrations. Docetaxel and ritonavir plasma concentrations were determined using liquid chromatography with tandem mass spectrometry. Safety was evaluated with the Common Terminology Criteria for Adverse Events, version 4.03.. In total, 16 patients completed the food-effect study. The geometric mean ratio (GMR) for the docetaxel area under the plasma concentration-time curve (AUC). The docetaxel and ritonavir exposure were not bioequivalent, as consumption of a high-fat meal prior to administration of ModraDoc006/r resulted in a slightly higher docetaxel exposure and lower ritonavir C. NCT03147378, date of registration: May 10 2017.

Topics: Administration, Oral; Aged; Antineoplastic Agents; Area Under Curve; Cross-Over Studies; Cytochrome P-450 CYP3A Inhibitors; Diarrhea; Diet, High-Fat; Docetaxel; Drug Combinations; Fasting; Fatigue; Female; Food-Drug Interactions; Humans; Hypokalemia; Male; Middle Aged; Neoplasms; Ritonavir; Tablets; Therapeutic Equivalency

Topics: Antiviral Agents; Betacoronavirus; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Drug Combinations; Drug Monitoring; Heart Conduction System; Humans; Hydroxychloroquine; Hypokalemia; Long QT Syndrome; Lopinavir; Magnesium; Pandemics; Pneumonia, Viral; Potassium; Retrospective Studies; Ritonavir; SARS-CoV-2

A 60-year-old HIV-1 infected woman on antiretroviral therapy (emtricitabine/tenofovir, and ritonavir-boosted atazanavir) developed Hodgkin's lymphoma. The patient initiated ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) chemotherapy and presented with neutropenia and severe hypokalemia. Hypokalemia was considered as part of a proximal tubular renal dysfunction, and other causes of hypokalemia were excluded. Due to suspicion of drug--drug interactions between antiretrovirals and vinblastine, ritonavir-boosted atazanavir was switched to dolutegravir and the patient continued emtricitabine/tenofovir. In the subsequent ABVD cycles, no neutropenia or hypokalemia were observed. Vinblastine is metabolized by the hepatic P450 cytochrome isoenzyme CYP3A4, therefore, concomitant administration with protease inhibitors may increase plasma levels of vinblastine. Vinblastine is also a substrate and inhibitor of multidrug resistance-associated protein 2 (MRP2) transporter in the proximal renal tubule. Inhibition of this renal transporter could increase tenofovir renal toxicity. Our hypothesis is that the hypokalemia could be a result of a tenofovir-mediated tubular damage triggered by the increased vinblastine serum levels secondary to a CYP3A4 inhibition by ritonavir. To the best of our knowledge, this is the first report of severe hypokalemia and proximal tubular renal dysfunction as a result of a possible drug-drug interaction between vinblastine, tenofovir and ritonavir-boosted atazanavir.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Dacarbazine; Doxorubicin; Drug Interactions; Emtricitabine; Female; HIV Infections; HIV Protease Inhibitors; Hodgkin Disease; Humans; Hypokalemia; Middle Aged; Ritonavir; Tenofovir; Treatment Outcome; Vinblastine

Although adverse events in HIV patients taking tenofovir are relatively rare, postmarketing reports of nephrotoxicity have alerted physicians to other potentially serious outcomes. We present a series of 40 patients who developed hypokalemia associated with tenofovir. Identified risk factors included concomitant ritonavir or didanosine use, a lower weight and longer duration of tenofovir use. Recovery or improvement was seen in the majority of patients (66%) after the discontinuation of tenofovir; however, four deaths occurred. The associated consequences of tenofovir-related hypokalemia may be profound and life-threatening.

Topics: Adenine; Adolescent; Adult; Body Weight; Child; Didanosine; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hypokalemia; Kidney Diseases; Male; Middle Aged; Organophosphonates; Reverse Transcriptase Inhibitors; Risk Factors; Ritonavir; Tenofovir; Time Factors