ritonavir and posaconazole

Complete delineation of the HIV-1 life cycle has resulted in the development of several antiretroviral drugs. Twenty-five therapeutic agents belonging to five different classes are currently available for the treatment of HIV-1 infections. Advent of triple combination antiretroviral therapy has significantly lowered the mortality rate in HIV patients. However, fungal infections still represent major opportunistic diseases in immunocompromised patients worldwide.. Antiretroviral drugs that target enzymes and/or proteins indispensable for viral replication are discussed in this article. Fungal infections, causative organisms, epidemiology and preferred treatment modalities are also outlined. Finally, observed/predicted drug-drug interactions between antiretrovirals and antifungals are summarized along with clinical recommendations.. Concomitant use of amphotericin B and tenofovir must be closely monitored for renal functioning. Due to relatively weak interactive potential with the CYP450 system, fluconazole is the preferred antifungal drug. High itraconazole doses (> 200 mg/day) are not advised in patients receiving booster protease inhibitor (PI) regimen. Posaconazole is contraindicated in combination with either efavirenz or fosamprenavir. Moreover, voriconazole is contraindicated with high-dose ritonavir-boosted PI. Echinocandins may aid in overcoming the limitations of existing antifungal therapy. An increasing number of documented or predicted drug-drug interactions and therapeutic drug monitoring may aid in the management of HIV-associated opportunistic fungal infections.

Topics: AIDS-Related Opportunistic Infections; Alkynes; Anti-Retroviral Agents; Antifungal Agents; Benzoxazines; Carbamates; Cyclopropanes; Drug Interactions; Drug Monitoring; Echinocandins; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Itraconazole; Mycoses; Organophosphates; Pyrimidines; Ritonavir; Sulfonamides; Triazoles; Voriconazole

Patients with HIV/AIDS are at increased risk for opportunistic fungal infections. These patients may require concomitant treatment with antiretrovirals and azole antifungals, and interactions between these classes of drugs should be anticipated.. A phase 1, open-label, randomized, crossover, drug interaction study was conducted to assess the pharmacokinetic effects of coadministration of posaconazole (400 mg twice daily), with atazanavir (ATV) (300 mg/d alone) and with ritonavir (100 mg/d) or with efavirenz (400 mg/d) in healthy volunteers.. Posaconazole increased maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of ATV by 2.6-fold and 3.7-fold, respectively. Posaconazole increased ATV Cmax and AUC when administered with ritonavir by 1.5-fold and 2.5-fold, respectively. Most subjects who received ATV (with and without ritonavir) and posaconazole experienced clinically relevant increases in total bilirubin. Coadministration of posaconazole and efavirenz resulted in clinically relevant decreases of posaconazole Cmax and AUC of approximately 45% and 50%, respectively.. Frequent monitoring of adverse events and toxicity related to antiviral exposure is recommended in the event of coadministration of posaconazole and ATV with or without ritonavir. In addition, because of decreased posaconazole exposure, coadministration with efavirenz should be avoided unless the benefit to patients outweighs the risk.

Topics: Administration, Oral; Adult; Alkynes; Anti-HIV Agents; Area Under Curve; Atazanavir Sulfate; Benzoxazines; Cross-Over Studies; Cyclopropanes; Drug Interactions; Female; Humans; Male; Middle Aged; Oligopeptides; Pyridines; Ritonavir; Triazoles

Solid dosage forms of amorphous solid dispersions (ASDs) have rarely been assessed for their crushability, although it might possibly be a more frequent practice than thought to facilitate oral administration in several clinical conditions (e.g. dysphagia) when no oral liquids of the same drug are available. Nevertheless, there are concerns that contraindicate these formulations' modification by grinding. For example, amorphous-amorphous phase separation, induction of crystallization, decreasing particle sizes, etc. might occur during grinding without knowing the implications on bioavailability. Hence, in this study, Sporanox® (itraconazole), Intelence® (etravirine), Noxafil® (posaconazole) and Norvir® (ritonavir), were selected as "model" enabling formulations (based on ASD) to evaluate if this concern was justified. Their assessment in simple and biorelevant media by two-stage in-vitro drug-release testing was performed which resulted in strong suspicion that pulverization is contradicted for some of these formulations. Despite differences were observed, uncertainty remains on the clinical relevance of these data as by golden standard it should still be confirmed by bioequivalence trials.

Topics: Administration, Oral; Antifungal Agents; Antiviral Agents; Biological Availability; Chemistry, Pharmaceutical; Crystallization; Drug Compounding; Drug Liberation; Equivalence Trials as Topic; Itraconazole; Nitriles; Particle Size; Pyridazines; Pyrimidines; Research Design; Ritonavir; Solubility; Therapeutic Equivalency; Triazoles; X-Ray Diffraction