Amit Desai

Pharmacokinetic Assessment of Drug-Drug Interactions of Isavuconazole With the Immunosuppressants Cyclosporine, Mycophenolic Acid, Prednisolone, Sirolimus, and Tacrolimus in Healthy Adults.

This report summarizes phase 1 studies that evaluated pharmacokinetic interactions between the novel triazole antifungal agent isavuconazole and the immunosuppressants cyclosporine, mycophenolic acid, prednisolone, sirolimus, and tacrolimus in healthy adults. Healthy subjects received single oral doses of cyclosporine (300 mg; n = 24), mycophenolate mofetil (1000 mg; n = 24), prednisone (20 mg; n = 21), sirolimus (2 mg; n = 22), and tacrolimus (5 mg; n = 24) in the presence and absence of clinical doses of oral isavuconazole (200 mg 3 times daily for 2 days; 200 mg once daily thereafter). Coadministration with isavuconazole increased the area under the concentration‐time curves (AUC0–∞) of tacrolimus, sirolimus, and cyclosporine by 125%, 84%, and 29%, respectively, and the AUCs of mycophenolic acid and prednisolone by 35% and 8%, respectively. Maximum concentrations (Cmax) of tacrolimus, sirolimus, and cyclosporine were 42%, 65%, and 6% higher, respectively; Cmax of mycophenolic acid and prednisolone were 11% and 4% lower, respectively. Isavuconazole pharmacokinetics were mostly unaffected by the immunosuppressants. Two subjects experienced elevated creatinine levels in the cyclosporine study; most adverse events were not considered to be of clinical concern. These results indicate that isavuconazole is an inhibitor of cyclosporine, mycophenolic acid, sirolimus, and tacrolimus metabolism.

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

This report describes the phase 1 trials that evaluated the metabolism of the novel triazole antifungal isavuconazole by cytochrome P450 3A4 (CYP3A4) and isavuconazoles effects on CYP3A4‐mediated metabolism in healthy adults. Coadministration of oral isavuconazole (100 mg once daily) with oral rifampin (600 mg once daily; CYP3A4 inducer) decreased isavuconazole area under the concentration‐time curve (AUCτ) during a dosing interval by 90% and maximum concentration (Cmax) by 75%. Conversely, coadministration of isavuconazole (200 mg single dose) with oral ketoconazole (200 mg twice daily; CYP3A4 inhibitor) increased isavuconazole AUC from time 0 to infinity (AUC0‐∞) and Cmax by 422% and 9%, respectively. Isavuconazole was coadministered (200 mg 3 times daily for 2 days, then 200 mg once daily) with single doses of oral midazolam (3 mg; CYP3A4 substrate) or ethinyl estradiol/norethindrone (35 μg/1 mg; CYP3A4 substrate). Following coadministration, AUC0‐∞ increased 103% for midazolam, 8% for ethinyl estradiol, and 16% for norethindrone; Cmax increased by 72%, 14%, and 6%, respectively. Most adverse events were mild to moderate in intensity; there were no deaths, and serious adverse events and adverse events leading to study discontinuation were rare. These results indicate that isavuconazole is a sensitive substrate and moderate inhibitor of CYP3A4.

Population Pharmacokinetics of Isavuconazole from Phase 1 and Phase 3 (SECURE) Trials in Adults and Target Attainment in Patients with Invasive Infections Due to Aspergillus and Other Filamentous Fungi

ABSTRACT Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent used for the treatment of invasive fungal infections. The objective of this analysis was to develop a population pharmacokinetic (PPK) model to identify covariates that affect isavuconazole pharmacokinetics and to determine the probability of target attainment (PTA) for invasive aspergillosis patients. Data from nine phase 1 studies and one phase 3 clinical trial (SECURE) were pooled to develop the PPK model (NONMEM, version 7.2). Stepwise covariate modeling was performed in Perl-speaks-NONMEM, version 3.7.6. The area under the curve (AUC) at steady state was calculated for 5,000 patients by using Monte Carlo simulations. The PTA using the estimated pharmacodynamic (PD) target value (total AUC/MIC ratio) estimated from in vivo PD studies of invasive aspergillosis over a range of MIC values was calculated using simulated patient AUC values. A two-compartment model with a Weibull absorption function and a first-order elimination process adequately described plasma isavuconazole concentrations. The mean estimate for isavuconazole clearance was 2.360 liters/h (percent coefficient of variation [%CV], 34%), and the mean AUC from 0 to 24 h (AUC0–24) was ∼100 mg·h/liter. Clearance was approximately 36% lower in Asians than in Caucasians. The PTA calculated over a range of MIC values by use of the nonneutropenic murine efficacy index corresponding to 90% survival indicated that adequate isavuconazole exposures were achieved in >90% of simulated patients to treat infections with MICs up to and including 1 mg/liter according to European Committee on Antimicrobial Susceptibility Testing methodology and in >90% of simulated patients for infections with MICs up to and including 0.5 mg/liter according to Clinical and Laboratory Standards Institute methodology. The highest MIC result for PTA was the same for Caucasian and Asian patients.

Population Pharmacokinetics of Isavuconazole in Subjects with Mild or Moderate Hepatic Impairment

ABSTRACT Isavuconazole, administered as the prodrug isavuconazonium sulfate, was recently approved by the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of adults with invasive aspergillosis and mucormycosis. The objective of this analysis was to develop a population pharmacokinetic model using NONMEM (version 7.2) for subjects with hepatic impairment, using intravenous and oral administration data from two hepatic studies, and to simulate concentration profiles to steady state, thus evaluating the need for dose adjustment. A two-compartment model with Weibull absorption function and first-order elimination process adequately described plasma isavuconazole concentrations. The population mean clearance in healthy subjects was 2.5 liters/h (5th and 95th percentiles: 2.0 and 3.1). The mean clearance values for subjects with mild and moderate hepatic impairment decreased approximately to 1.55 liters/h (5th and 95th percentiles: 1.3 and 1.8 liters/h) and 1.32 liters/h (5th and 95th percentiles: 1.05 and 1.35), respectively. Peripheral volume of distribution increased with body mass index. Simulations of mean concentration time profiles to steady state showed less than a 2-fold increase in mean trough concentrations for subjects with mild and moderate hepatic impairment compared with healthy subjects. After administration of the single dose, safety data for subjects with mild and moderate hepatic impairment were generally comparable to those for healthy subjects in both studies. Due to the <2-fold increase in trough concentrations and the established safety margin, dose adjustment appears to be unnecessary in subjects with mild or moderate hepatic impairment.

Pharmacodynamics of isavuconazole in experimental invasive pulmonary aspergillosis: implications for clinical breakpoints

OBJECTIVES Isavuconazole, a novel triazole antifungal agent, has broad-spectrum activity against Aspergillus spp. and other pathogenic fungi. The isavuconazole exposure-response relationship in experimental invasive pulmonary aspergillosis using galactomannan index (GMI) suppression as a marker of disease clearance was explored. METHODS The impact of exposure on GMI suppression in persistently neutropenic rabbits treated with isavuconazonium sulphate (isavuconazole-equivalent dosages of 20, 40 or 60 mg/kg every 24 h, after a 90 mg/kg loading dose) for 12 days was linked using mathematical modelling. Bridging to humans using population pharmacokinetic (PK) data from a clinical trial in invasive aspergillosis was performed using Monte Carlo simulations. RESULTS Mean plasma isavuconazole AUC/MIC (EC50) of 79.65 (95% CI 32.2, 127.1) produced a half-maximal effect in GMI suppression. The inhibitory sigmoid Emax curve dropped sharply after an AUC/MIC of ≥30 and was near maximum (EC80) at ∼130. Bridging the experimental PK/pharmacodynamic (PD) target to human population PK data was then used to return to the rabbit model to determine a clinically relevant PD endpoint. The clinical dosing regimen used in the trial would result in a mean GMI of 4.3 ± 1.8, which is a 50% reduction from the starting GMI in the experiment. CONCLUSIONS The clinical trial results showing the non-inferiority of isavuconazole to voriconazole for all-cause mortality further support the PK-PD endpoint, thereby demonstrating the usefulness of the rabbit model and endpoint for isavuconazole and implications on interpretive breakpoints. Importantly, the analysis supports this model as an important tool for development of antifungal agents.

Isavuconazole absorption following oral administration in healthy subjects is comparable to intravenous dosing, and is not affected by food, or drugs that alter stomach pH.

OBJECTIVE/METHODS Two openlabel, single-dose, randomized crossover studies and one open-label, multiple-dose, parallel group study in healthy volunteers were conducted with the prodrug, isavuconazonium sulfate, to determine absolute bioavailability of the active triazole, isavuconazole (EudraCT 2007-004949-15; n = 14), and the effect of food (EudraCT 2007- 004940-63; n = 26), and pH (NCT02128893; n = 24) on the absorption of isavuconazole. Isavuconazonium sulfate 744 mg designed to deliver 400 mg of the active triazole isavuconazole was administered in the absolute bioavailability (oral or intravenous (IV) (2-hour infusion)) and food-effect studies (oral). In the pH-effect study, isavuconazonium sulfate 372 mg designed to deliver 200 mg of isavuconazole was administered orally three times daily (t.i.d.) for 2 days, followed by a single daily oral dose for 3 days, in the presence of steady state esomeprazole dosed orally at 40 mg/day. RESULTS Isavuconazole was well tolerated in each study. Bioavailability: Geometric least squares mean ratios (GLSMR; oral/IV) for isavuconazole AUC∞, and Cmax were 98% (90% confidence interval (CI): 94, 101) and 78% (90% CI: 72, 85), respectively. Food-effect: GLSMR (fed/fasted) for AUC∞ and Cmax of isavuconazole in plasma were 110% (90% CI: 102, 118) and 92% (90% CI: 86, 98), respectively. Median tmax was 5 hours with food and 3 hours under fasted conditions. pH-effect: GLSMR for isavuconazole AUCtau and Cmax were 108% (90% CI: 89, 130) and 105% (90% CI: 89, 124), respectively. CONCLUSIONS Orally administered isavuconazonium sulfate effectively delivers isavuconazole, as evidenced by the fact that oral isavuconazole is bioequivalent to the IV formulation. Dose adjustments are not required when switching between oral and IV formulations, regardless of food or drugs that increase gastric pH.

Pharmacokinetic Interactions Between Isavuconazole and the Drug Transporter Substrates Atorvastatin, Digoxin, Metformin, and Methotrexate in Healthy Subjects

This article summarizes 4 phase 1 trials that explored interactions between the novel, triazole antifungal isavuconazole and substrates of the drug transporters breast cancer resistance protein (BCRP), multidrug and toxin extrusion protein‐1 (MATE1), organic anion transporters 1/3 (OAT1/OAT3), organic anion‐transporting polypeptide 1B1 (OATP1B1), organic cation transporters 1/2 (OCT1/OCT2), and P‐glycoprotein (P‐gp). Healthy subjects received single doses of atorvastatin (20 mg; OATP1B1 and P‐gp substrate), digoxin (0.5 mg; P‐gp substrate), metformin (850 mg; OCT1, OCT2, and MATE1 substrate), or methotrexate (7.5 mg; BCRP, OAT1, and OAT3 substrate) in the presence and absence of clinical doses of isavuconazole (200 mg 3 times a day for 2 days; 200 mg once daily thereafter). Coadministration with isavuconazole increased mean area under the plasma concentration‐time curves (90% confidence interval) of atorvastatin, digoxin, and metformin to 137% (129, 145), 125% (117, 134),  and 152% (138, 168) and increased mean maximum plasma concentrations to 103% (88, 121), 133% (119, 149), and 123% (109, 140), respectively. Methotrexate parameters were unaffected by isavuconazole. There were no serious adverse events. These findings indicate that isavuconazole is a weak inhibitor of P‐gp, as well as OCT1, OCT2, MATE1, or a combination thereof but not of BCRP, OATP1B1, OAT1, or OAT3.

Pharmacokinetic Effects of Isavuconazole Coadministration With the Cytochrome P450 Enzyme Substrates Bupropion, Repaglinide, Caffeine, Dextromethorphan, and Methadone in Healthy Subjects

This report describes phase 1 clinical trials performed to assess interactions of oral isavuconazole at the clinically targeted dose (200 mg, administered as isavuconazonium sulfate 372 mg, 3 times a day for 2 days; 200 mg once daily [QD] thereafter) with single oral doses of the cytochrome P450 (CYP) substrates: bupropion hydrochloride (CYP2B6; 100 mg; n = 24), repaglinide (CYP2C8/CYP3A4; 0.5 mg; n = 24), caffeine (CYP1A2; 200 mg; n = 24), dextromethorphan hydrobromide (CYP2D6/CYP3A4; 30 mg; n = 24), and methadone (CYP2B6/CYP2C19/CYP3A4; 10 mg; n = 23). Compared with each drug alone, coadministration with isavuconazole changed the area under the concentration‐time curves (AUC∞) and maximum concentrations (Cmax) as follows: bupropion, AUC∞ reduced 42%, Cmax reduced 31%; repaglinide, AUC∞ reduced 8%, Cmax reduced 14%; caffeine, AUC∞ increased 4%, Cmax reduced 1%; dextromethorphan, AUC∞ increased 18%, Cmax increased 17%; R‐methadone, AUC∞ reduced 10%, Cmax increased 3%; S‐methadone, AUC∞ reduced 35%, Cmax increased 1%. In all studies, there were no deaths, 1 serious adverse event (dextromethorphan study; perioral numbness, numbness of right arm and leg), and adverse events leading to study discontinuation were rare. Thus, isavuconazole is a mild inducer of CYP2B6 but does not appear to affect CYP1A2‐, CYP2C8‐, or CYP2D6‐mediated metabolism.

Pharmacokinetic and Pharmacodynamic Evaluation of the Drug-Drug Interaction Between Isavuconazole and Warfarin in Healthy Subjects.

This phase 1 trial evaluated pharmacokinetic and pharmacodynamic interactions between the novel triazole antifungal agent isavuconazole and warfarin in healthy adults. Multiple doses of isavuconazole were administered as the oral prodrug, isavuconazonium sulfate (372 mg 3 times a day for 2 days loading dose, then 372 mg once daily thereafter; equivalent to isavuconazole 200 mg), in the presence and absence of single doses of oral warfarin sodium 20 mg. Coadministration with isavuconazole increased the mean area under the plasma concentration‐time curves from time 0 to infinity of S‐ and R‐warfarin by 11% and 20%, respectively, but decreased the mean maximum plasma concentrations of S‐ and R‐warfarin by 12% and 7%, respectively, relative to warfarin alone. Mean area under the international normalized ratio curve and maximum international normalized ratio were 4% lower in the presence vs absence of isavuconazole. Mean warfarin area under the prothrombin time curve and maximum prothrombin time were 3% lower in the presence vs absence of isavuconazole. There were no serious treatment‐emergent adverse events (TEAEs), and no subjects discontinued the study due to TEAEs. All TEAEs were mild in intensity. These findings indicate that coadministration with isavuconazole has no clinically relevant effects on warfarin pharmacokinetics or pharmacodynamics.

Drug-drug interactions between triazole antifungal agents used to treat invasive aspergillosis and immunosuppressants metabolized by cytochrome P450 3A4

Patients undergoing treatment with immunosuppressant drugs following solid organ or hematopoietic stem cell transplantation are at particular risk for development of serious infections such as invasive aspergillosis. Four triazole antifungal drugs, voriconazole, posaconazole, itraconazole, and isavuconazole, are approved to treat invasive aspergillosis either as first‐ or second‐line therapy. All of these agents are inhibitors of cytochrome P450 3A4, which plays a key role in metabolizing immunosuppressant drugs such as cyclosporine, tacrolimus, and sirolimus. Thus, co‐administration of a triazole antifungal drug with these immunosuppressant drugs can potentially increase plasma concentrations of the immunosuppressant drugs, thereby resulting in toxicity, or upon discontinuation, inadvertently decrease the respective concentrations with increased risk of rejection or graft‐versus‐host disease. In this article, we review the evidence for the extent of inhibition of cytochrome P450 3A4 by each of these triazole antifungal drugs and assess their effects on cyclosporine, tacrolimus, and sirolimus. We also consider other factors affecting interactions of these two classes of drugs. Finally, we examine recommendations and strategies to evaluate and address those potential drug‐drug interactions in these patients.