Pharmacokinetic Interaction Between Isavuconazole and a Fixed‐Dose Combination of Lopinavir 400 mg/Ritonavir 100 mg in Healthy Subjects

Abstract

This phase 1, open‐label study evaluated the pharmacokinetic effects of coadministration of the antifungal agent, isavuconazole (administered as its water‐soluble prodrug isavuconazonium sulfate), with the antiretroviral agent lopinavir/ritonavir in healthy adults. In part 1, 13 subjects were randomized to 2 arms to receive multiple doses of oral isavuconazole 100 mg either alone or with lopinavir/ritonavir 400/100 mg. In part 2, a different group of 55 subjects were randomized to 3 arms to receive multiple doses of oral isavuconazole 200 mg, either alone or with lopinavir/ritonavir 400/100 mg, or to receive oral lopinavir/ritonavir 400/100 mg alone. Mean area under the concentration‐time curve (AUC) following the last dose (AUCτ) and Cmax of isavuconazole increased by 113% and 96% in part 1 and by 96% and 74% in part 2 in the presence vs absence of lopinavir/ritonavir, respectively. Mean AUCτ and Cmax of lopinavir were 27% and 23% lower, and mean AUCτ and Cmax of ritonavir were 31% and 33% lower in the presence vs absence of isavuconazole, respectively. Mild to moderate gastrointestinal disorders were the most common adverse events experienced. These findings indicate that coadministration of lopinavir/ritonavir with isavuconazole can decrease the exposure of lopinavir/ritonavir and increase the exposure of isavuconazole. Patients should be monitored for reduced antiviral efficacy if these agents are coadministered.

Pharmacokinetic Evaluation of CYP3A4‐Mediated Drug‐Drug Interactions of Isavuconazole With Rifampin, Ketoconazole, Midazolam, and Ethinyl Estradiol/Norethindrone in Healthy Adults

“…Blood samples were collected for PK analysis of rifampin on day 43 at predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 24, and 48 hours postdose. Blood samples were collected for PK analysis of isavuconazole on days 14 and 57 at predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6,8,10,12,14,16,24,48,72,96,144,192,240,288, and 336 hours postdose.…”

The ‘cephalosporin era’ of triazole therapy: isavuconazole, a welcomed newcomer for the treatment of invasive fungal infections

“…The study included adults ( ‡ 18 years old) with possible, probable, or proven disease according to consensus criteria [66]. Exclusion criteria were patients with other invasive fungal diseases (neither Aspergillus nor filamentous fungi), hepatic or moderate to severe renal dysfunction, chronic aspergillosis, aspergilloma or allergic bronchopulmonary aspergillosis, " Tacrolimus 2.25-fold [63] No effect on prednisolone [62] " Atorvastatin by~1.4-fold [79] " Midazolam 2.05 fold [10] # Lopinavir 27%, ritonavir 31% [80] …”

Isavuconazole for the treatment of invasive aspergillosis and mucormycosis: current evidence, safety, efficacy, and clinical recommendations

“…Thus, therapeutic drug monitoring of such drugs is indicated with concomitant use of ISZ. Drugs that are P -glycoprotein substrates (eg, digoxin, colchicine, mycophenolate) may need dosage adjustment and close monitoring of serum levels to avoid toxicities 74–77…”