Pharmacokinetic Interaction Between Isavuconazole and a Fixed-Dose Combination of Lopinavir 400 mg/Ritonavir 100 mg in Healthy Subjects.
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 Cmaxof 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 AUCτand Cmaxof lopinavir were 27% and 23% lower, and mean AUCτand Cmaxof 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.
Astellas Pharma Global Development, Inc, Northbrook, IL, USA.
Takao
T
Yamazaki
Astellas Pharma Global Development, Inc, Northbrook, IL, USA.
Amit
A
Desai
PAREXEL, Los Angeles, CA, USA.
David
D
Han
Analysis & Pharmacokinetics Research Laboratories, Astellas Pharma Inc, Osaka, Japan.
Kota
K
Kato
Astellas Pharma Global Development, Inc, Northbrook, IL, USA.
Donna
D
Kowalski
Astellas Pharma Global Development, Inc, Northbrook, IL, USA.
Shahzad
S
Akhtar
Astellas Pharma Global Development, Inc, Northbrook, IL, USA.
Christopher
C
Lademacher
Astellas Pharma Global Development, Inc, Northbrook, IL, USA.
Laura
L
Kovanda
Astellas Pharma Global Development, Inc, Northbrook, IL, USA.
Robert
R
Townsend
D000328:Adult; D019540:Area Under Curve; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D061466:Lopinavir / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D011725:Pyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D011897:Random Allocation; D019438:Ritonavir / Q000008:administration & dosage*; D014230:Triazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D055815:Young Adult
D004338:Drug Combinations; D009570:Nitriles; D011725:Pyridines; D014230:Triazoles; D061466:Lopinavir; C508735:isavuconazole; D019438:Ritonavir
HIV-1; isavuconazole; lopinavir; pharmacokinetics; ritonavir