No Dose Adjustment for Isavuconazole Based on Age or Sex.

This phase 1, open-label, single-dose, parallel-group study evaluated the pharmacokinetics (PK) of isavuconazole after a single oral dose of the prodrug isavuconazonium sulfate in healthy nonelderly (age, 18 to 45 years) and elderly (age, ≥65 years) males and females. Overall, 48 subjects were enrolled in the study (n = 12 each in groups of nonelderly males and females and elderly males and females). All subjects received a single oral dose of 372 mg of isavuconazonium sulfate (equivalent to 200 mg isavuconazole). PK samples were collected for analysis of isavuconazole plasma concentrations from the predose time point up to 336 h postdose. Data were analyzed using population pharmacokinetic (PPK) analysis. The resulting PPK model included two compartments with Weibull absorption function as well as interindividual variability with respect to clearance, intercompartment clearance, volumes of central and peripheral compartments, and two Weibull absorption parameters, RA and KAMAX. The PPK analysis showed that elderly females had the highest exposure versus males (ratio of total area under the time-concentration curve [AUC], 138; 90% confidence interval [CI], 118 to 161) and versus nonelderly females (ratio of AUC, 147; 90% CI, 123 to 176). Higher exposures in elderly females were not associated with significant toxicity or treatment-emergent adverse events, as measured in this study. No dose adjustments appear to be necessary based on either age group or sex even with an increase in exposure for elderly females. (This study has been registered at ClinicalTrials.gov under registration no. NCT01657890.).

Exposure-Response Relationships for Isavuconazole in Patients with Invasive Aspergillosis and Other Filamentous Fungi.

Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent for the treatment of invasive fungal infections. The purpose of this analysis was to characterize the isavuconazole exposure-response relationship for measures of efficacy and safety in patients with invasive aspergillosis and infections by other filamentous fungi from the SECURE clinical trial. Two hundred thirty-one patients who received the clinical dosing regimen and had exposure parameters were included in the analysis. The primary drug exposure parameters included were predicted trough steady-state plasma concentrations, predicted trough concentrations after 7 and 14 days of drug administration, and area under the curve estimated at steady state (AUCss). The exposure parameters were analyzed against efficacy endpoints that included all-cause mortality through day 42 in the intent-to-treat (ITT) and modified ITT populations, data review committee (DRC)-adjudicated overall response at end of treatment (EOT), and DRC-adjudicated clinical response at EOT. The safety endpoints analyzed were elevated or abnormal alanine aminotransferase, increased aspartate aminotransferase, and a combination of the two. The endpoints were analyzed using logistic regression models. No statistically significant relationship (P > 0.05) was found between isavuconazole exposure and either efficacy or safety endpoints. The lack of association between exposure and efficacy indicates that the isavuconazole exposures achieved by clinical dosing were appropriate for treating the infecting organisms in the SECURE study and that increases in alanine or aspartate aminotransferase were not related to increase in exposures. Without a clear relationship, there is no current clinical evidence for recommending routine therapeutic drug monitoring for isavuconazole.

Safety and tolerability of intravenous regadenoson in healthy subjects: A randomized, repeat-dose, placebo-controlled study.

BACKGROUND: Regadenoson is a selective A2A adenosine receptor agonist indicated for radionuclide myocardial perfusion imaging in patients unable to undergo adequate exercise stress. However, the safety, tolerability, and plasma concentrations associated with repeated doses have not previously been assessed. METHOD AND RESULTS: Healthy males and females were randomized to receive intravenous regadenoson [100 µg (3 doses), 200 µg (3 doses), or 400 µg (2 doses)], or placebo (2 or 3 doses; 0.9% sodium chloride); all doses 10 minutes apart. The primary endpoint was vital sign measurements (blood pressure and heart rate). Secondary endpoints included 12-lead electrocardiogram measurements, clinical laboratory evaluations (hematology, chemistry, and urinalysis), and adverse events. Thirty-six subjects were randomized and completed the study. Plasma concentrations of regadenoson increased in a dose-related manner and with successive doses. No consistent effect was observed for systolic blood pressure, although diastolic blood pressure was slightly lower than placebo for all regadenoson groups. Transient, dose-dependent increases in heart rate were observed in all regadenoson groups. There were no serious adverse events; 27 adverse events occurred in 14 regadenoson-treated subjects vs two events in two placebo-treated subjects. CONCLUSION: Repeated doses of regadenoson appeared to be safe and well tolerated in healthy subjects.

Phase I trial to investigate the effect of renal impairment on isavuconazole pharmacokinetics.

PURPOSE: The purpose of the study is to evaluate the effect of renal impairment (RI) and end-stage renal disease (ESRD) on the pharmacokinetics (PK) of isavuconazole and the inactive cleavage product, BAL8728. METHODS: A single intravenous dose of the prodrug isavuconazonium sulfate (372 mg, equivalent to 200 mg isavuconazole and 75 mg of BAL8728 cleavage product) was administered to healthy controls (parts 1 and 2) and participants with mild, moderate, or severe RI (part 2) or ESRD (part 1); ESRD participants received two doses of 200 mg isavuconazole, 1 h post-dialysis (day 1) and prior to dialysis (day 15). Plasma PK parameters for isavuconazole included maximum concentration (C max), area under the concentration-time curve (AUC) from time of dose to 72 h (AUC72), AUC extrapolated to infinity (AUC∞), AUC to last measurable concentration (AUClast), half-life (t ½ h), volume of distribution (V z), and total clearance (CL), for the healthy control group versus those with mild, moderate, or severe RI or ESRD. RESULTS: Isavuconazole C max values were 4% higher in mild RI and 7, 14, and 21% lower in participants with moderate RI, severe RI, or ESRD versus the healthy control group, respectively. When hemodialysis occurred post-dose (day 15), participants with ESRD had a 30% increase in AUC72 for isavuconazole in parallel with reduction of extracellular volume induced by dialysis. Exposure (AUC∞ and AUClast) was not significantly different for participants with mild, moderate, or severe RI versus healthy controls although there was considerable variability. The t1/2 (day 1) was 125.5 ± 63.6 h (healthy control group), 204.5 ± 82.6 h (ESRD group) in part 1, and 140.5 ± 77.7 h (healthy control group), 117.0 ± 66.2 h (mild RI), 158.5 ± 56.4 h (moderate RI), and 145.8 ± 65.8 L/h (severe RI) in part 2. CL was 2.4 ± 0.8 L/h (healthy control group) and 2.9 ± 1.3 L/h (ESRD group) in part 1 and 2.4 ± 1.2 L/h (healthy control group), 2.5 ± 1.0 L/h (mild RI), 2.2 ± 0.8 L/h (moderate RI), and 2.4 ± 0.8 L/h (severe RI) in part 2. The V z was 382.6 ± 150.6 L in the healthy control group and 735.6 ± 277.3 L in ESRD patients on day 1 in part 1 of the study. In part 2 of the study, V z was 410.8 ± 89.7 L in the healthy control group, 341.6 ± 72.3 L in mild RI, 509.1 ± 262.2 L in moderate RI, and 439.4 L in severe RI. CONCLUSIONS: Based on the findings of this study, dose adjustments of isavuconazole are unlikely to be required in individuals with RI or in those with ESRD who receive hemodialysis.

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.

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.

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.

Reproducibility of QTc interval changes after meal intake.

BACKGROUND: Detection of QTc decreases after meal intake was proposed as a possible proof of assay sensitivity in studies of drug-induced QTc changes. However, day-to-day reproducibility of QTc decreases after meal intake has not been established. METHODS: Holter recordings were available from 4 different baseline drug-free days of a thorough QT study in 157 females and 164 males. During each of the baselines, subjects were fasting in the morning and were served standardized lunch. Heart rates and QTc intervals were measured during repeated time-points throughout each study day. Two investigations were performed. In the first investigation, 3 heart rate and QTc measurements 1, 2, and 3h after lunch were averaged in each subject and corrected for the morning fasting baseline. Reproducibility of heart rate and QTc changes after the meal on different days X and Y was assessed by normalized repeatability coefficients 2*|MX-MY|/|MX+MY|, where MX and MY are measurements in the same subject on days X and Y, respectively. These were compared for heart rate and QTc changes after meal for different pairs of baseline days. In the second investigation, 36 females and 41 males were considered who received moxifloxacin during the source thorough QT study. The QTc increases after moxifloxacin were expressed by averaging 3 time-point values and corrected for placebo QTc values measured 25days apart. In the same subjects, QTc readings after lunch were also corrected for fasting baseline readings 25days apart. QTc responses to moxifloxacin and to meal intake were compared. RESULTS: Repeatability of QTc decreases after meal was significantly (p<0.0000001) poorer than that of heart rate increases after meal. Of the subjects receiving moxifloxacin during the study, 6% did not show QTc prolongation on moxifloxacin while 39% have not shown QTc shortening after lunch (p<0.00001). CONCLUSION: The reproducibility of QTc changes after meal is limited. The power of proving QTc assay sensitivity by the detection of QTc changes after meal is poorer than the power of the standard moxifloxacin-based assay sensitivity.

ICH E14-compatible holter bin method and its equivalence to individual heart rate correction in the assessment of drug-induced QT changes.

INTRODUCTION: The Holter bin method evaluates QT interval changes in the presence of heart rate changes without correcting the QT interval. However, the method does not allow time-matched comparisons, thus contradicting available guidance and good practice. We report a modification of the methods that allows time-matched comparisons without any heart rate correction. METHODS AND RESULTS: The modified Holter bin method (a) finds matching baseline heart rates for each QT reading on treatment and (b) calculates ΔQT values from the QT intervals on baseline and on treatment that match in heart rates. The difference between ΔQT values on active treatment and placebo provides the ΔΔQT value. The method was compared with the individual correction method in the data of the mirabegron thorough QT study in which supratherapeutic doses of this ß3-adrenoceptor agonist led to substantial heart rate changes. The modified Holter bin method reproduced closely the results obtained with the individual heart rate correction. At all time points of the mirabegron study, the differences between the mean ΔΔQT values by the Holter bin method and the individual correction method were below 1 millisecond. Compared to the individual correction, the Holter bin method led to slight increases in the standard deviations of ΔΔQT values, but these were on average below 0.25 millisecond. CONCLUSIONS: The Holter bin methodology can be modified to make it compatible with the available guidance and with good practice of clinical investigations. The results obtained with the modified Holter bin method are practically the same as with individualized heart rate corrected QT intervals. The close correspondence between the 2 methods demonstrates that the present possibilities of comparing QT interval duration in the presence of experiment-induced heart rate differences are not influenced by methodological artifacts.

QTc changes after meal intake: sex differences and correlates.

BACKGROUND: Detection of food-induced QTc shortening has been proposed as an assay sensitivity in thorough QT/QTc (TQT) studies. Data of a large clinical study were used to investigate the food effects on QTc intervals. METHODS: Day-time drug-free 12-lead Holter recordings starting around 8:20AM were repeated 4 times in each of 176 female and 176 male healthy subjects aged 32.7±9.1years. The recordings contained 16 episodes during which the subjects were in strict supine position. Heart rate and QTc intervals individually corrected for rate and QT/RR hysteresis were measured during these episodes and averaged over the 4 repeated recordings. In the morning hours, the subjects were fasting. Standardized lunch and dinner were served at around 2:00PM and 7:30PM, respectively. Heart rate and QTc changes induced by lunch and dinner were assessed by calculating the differences of averaged measurements from 2hours before till 2hours after the meals. RESULTS: In women, lunch and dinner led to statistically significant heart rate accelerations by 11.0±4.0 and 6.8±3.4 beats per minute [bpm], respectively. In men, the corresponding significant heart rate accelerations were by 9.9±3.4 and 4.5±2.6bpm, respectively. On the contrary, the QTc responses to both meals were inconsistent. After lunch, QTc intervals shortened significantly by 2.87±3.46ms and 0.79±3.64ms in women and men, respectively. However, after dinner, QTc intervals prolonged significantly by 4.69±3.66ms and 3.53±2.88ms in women and men, respectively. CONCLUSIONS: There were systematic changes in individually corrected QTc intervals with QTc shortening after lunch and QTc lengthening after dinner, both in women and men. Because of these divergent diurnal effects, the use of meal-induced QTc changes to prove the assay sensitivity in TQT studies requires further evaluation.

QT/RR curvatures in healthy subjects: sex differences and covariates.

Data of a large clinical study were used to investigate how much are the QT/RR patterns in healthy subjects curved and whether these curvatures differ between women and men. Daytime drug-free 12-lead Holter recordings were repeated 4 times in each of 176 female healthy subjects and 176 male healthy subjects aged 32.7 ± 9.1 yr. In each of the subjects, up to 1,440 carefully verified QT interval measurements were obtained with QT/RR hysteresis-corrected RR intervals. Individual subject data were used to fit the following regression equation: QT = χ + (δ/γ)(1 - RR(γ)) + ε, where QT and RR are QT and RR measurements (in s), χ is regression intercept, δ is the QT/RR slope, γ is the QT/RR curvature and provides the lowest regression residual, and ε represents normally distributed zero-centered errors. The bootstrap technique showed the intrasubject reproducibility of QT/RR slopes and curvatures. In women and men, QT/RR curvatures were 0.544 ± 0.661 and 0.797 ± 0.706, respectively (P = 0.0006). The corresponding QT/RR slopes were 0.158 ± 0.030 and 0.139 ± 0.023, respectively (P < 0.0001). QT/RR curvatures were related to QT/RR slopes but not to individually corrected mean QTc intervals or individual QT/RR hysteresis profiles. The individual heart rate correction formula derived from the curvilinear regression provided a significantly lower intrasubject variability of QTc interval than individual optimisation of linear or log-linear QT/RR heart rate corrections. The QT/RR curvature can be reliable measured and expressed numerically. The corresponding heart rate correction formula provides more compact data than the previously proposed approaches. There are substantial sex differences in QT/RR patterns. Women have a QT/RR pattern that is not only steeper than men but also more curved.

Relationship of QT interval variability to heart rate and RR interval variability.

The study investigated whether the beat-to-beat QT interval variability relationship to the mean heart rate and the RR interval variability depended on the cardiovascular autonomic status changed by postural positioning. Repeated long-term 12-lead Holter recordings were obtained from 352 healthy subjects (mean age 32.7 ± 9.1 years, 176 females) while they underwent postural provocative tests involving supine, unsupported sitting and unsupported standing positions. Each recording was processed as a sequence of overlapping 10-second segments. In each segment, the mean RR interval, the coefficients of variance of the RR intervals (RRCV) and the QT intervals (QTCV) were obtained. In each subject, these characteristics, corresponding to different postural positions, were firstly averaged and secondly used to obtain within-subject correlation coefficients between the different characteristics at different postural positions. While the within-subject means of RRCV generally decreased when changing the position from supine to sitting and to standing (4.53 ± 1.95%, 4.12 ± 1.51% and 3.26 ± 1.56% in females and 3.99 ± 1.44%, 4.00 ± 1.24% and 3.53 ± 1.32% in males respectively), the means of QTCV systematically increased during these position changes (0.96 ± 0.40%, 1.30 ± 0.56% and 1.88 ± 1.46% in females and 0.85 ± 0.30%, 1.13 ± 0.41% and 1.41 ± 0.59% in males, respectively). The intra-subject relationship between QTCV, RRCV and mean RR intervals was highly dependent on postural positions. The study concludes that no universally applicable normalization of the QT interval variability for the heart rate and/or the RR interval variability should be assumed. In future studies of the QT variability, it seems preferable to report on the absolute values of QT variability, RR variability and mean heart rate separately.

Single dose pharmacokinetics and absolute bioavailability of mirabegron, a ß3-adrenoceptor agonist for treatment of overactive bladder.

BACKGROUND AND OBJECTIVES: Mirabegron is a potent and selective ß3-adrenoceptor agonist in development for treatment of overactive bladder. METHODS: Mirabegron pharmacokinetics after single intravenous (i.v.) and oral doses, absolute bioavailability (F), dose proportionality, sex differences and tolerability were assessed in 2 single-dose, open-label, randomized, parallel-group, cross-over studies in healthy men (exploratory Study 1, n = 12) and men and women (Study 2, n = 91). RESULTS: After oral dosing (25 - 150 mg), peak plasma concentrations were attained after ~ 4 h. Mean half-life was around 40 h for both routes of administration. Volume of distribution at steady state was 1,670 l and total clearance was around 57 l/h for i.v. dosing. Mirabegron pharmacokinetics were linear after i.v. dosing (7.5 - 50 mg), but exposure increased more than proportionally after oral dosing due to increased F (29% for 25 mg to 45% at 150 mg). About 20% of the (absorbed) dose was excreted unchanged into urine. Area under the curve (AUC) was 27% and 64% higher in females than males after i.v. and oral dosing respectively; differences were mostly attributed to body weight, and for oral dosing, also to F. CONCLUSIONS: Mirabegron pharmacokinetics were linear after i.v. dosing (7.5 - 50 mg), but increased more than proportionally after oral dosing (25 - 150 mg) as a result of increased F. Sex differences in exposure could be explained by body weight and for oral dosing, also by F. Mirabegron was in general well tolerated up to the highest doses studied, 50 mg i.v. and 150 mg oral.

Importance of subject-specific QT/RR curvatures in the design of individual heart rate corrections of the QT interval.

OBJECTIVE: A statistical modelling study investigated whether incorporating the curvatures of QT/RR patterns into the individual-specific QT heart rate correction increases QTc data accuracy. METHODS: Repeated ECG readings were available from 4 different drug-free recordings made in 176+176 healthy female and male subjects (aged 32 ± 10 and 33 ± 8 years, respectively). In each subject, up to 1440 ECG readings were made of QT intervals and of the corresponding QT/RR hysteresis corrected RR intervals. The QT/RR patterns of each study participant was fitted with 12 different regression formulae that corresponded to differently curved physiologically plausible QT/RR profiles. In each subject, each of the regression fits was converted into a QT heart rate correction formula and the optimum model that fitted the data of the subject best was identified. Correction formulae were applied to modelled QT/RR data with RR intervals between 400 ms and 1600 ms. Differences in QTc intervals calculated by the correction formulae corresponding to the individually optimum QT/RR regression models and by the same type of regression in all study subjects were statistically summarised in females and males. RESULTS: Compared to the individually curvature optimised QTc heart rate correction formulae, formulae of the different regression models overestimated or underestimated the QTc values when applied on all study subjects. At RR of 500 ms, the model assuming linear QT/RR relationship led to errors of -5.01 ± 6.63 ms and of -4.80 ± 7.23 ms in females and males, respectively. At the same RR interval level, the model assuming the linear relationship between the logarithms of QT and RR intervals led to errors of +11.51 ± 6.36 ms and of +15.09 ± 7.61 ms in females and males, respectively. CONCLUSION: The differences in the curvatures of QT/RR patterns should be considered in the optimisation of subject-specific heart rate corrections. Forcing an arbitrary simple regression model on the QT/RR patterns of different subjects may lead to appreciable errors in QTc estimates. The frequently used linear and log-linear regression models were among the least precise if used without checking their appropriateness in individual subjects.

Time-dependent inhibitory effects of (1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-1,14-dihydroxy-12-(E)-2-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylvinyl-23,25-dimethoxy-13,19,21,27-tetramethyl-17-(2-oxopropyl)-11,28-dioxa-4-azatricyclo[22.3.1.0(4.9)]octacos-18-ene-2,3,10,16-tetrone (FK1706), a novel nonimmunosuppressive immunophilin ligand, on CYP3A4/5 activity in humans in vivo and in vitro.

We investigated the inhibitory effects of (1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-1, 14-dihydroxy-12-(E)-2-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylvinyl-23,25-dimethoxy-13,19,21,27-tetramethyl-17-(2-oxopropyl)-11,28-dioxa-4-azatricyclo [22.3.1.0(4.9)]octacos-18-ene-2,3,10,16-tetrone (FK1706), a novel nonimmunosuppressive immunophilin ligand, on CYP3A4/5 in in vitro and in vivo settings. First, the inhibitory effects of FK1706 (preincubation dependence, inactivation rate estimation, and reversibility) were tested using human liver microsomes. Second, the effect of repeated oral doses of FK1706 (60 mg q.d. for 14 days) on the pharmacokinetics of midazolam (single oral 2-mg dose) was tested in healthy volunteers. Finally, pharmacokinetic modeling and simulation were performed. In vitro experiments showed that FK1706 inhibited CYP3A4/5 in a time-dependent and irreversible manner. The in vitro maximum inactivation rate constant (k(inact)) and concentration of inhibitor that gave half-maximal k(inact) (K(I)) were estimated to be 10.1 h(-1) and 2050 ng/ml, respectively. In the clinical study, FK1706 produced a 2-fold increase in the area under the time-concentration curve (AUC) of midazolam. A pharmacokinetic model developed for this study, which described the time course of concentrations of both FK1706 and midazolam and incorporated CYP3A4/5 inactivation in the liver and intestine, successfully predicted the change in the pharmacokinetics of midazolam using in vitro k(inact) and K(I) values (1.66- to 2.81-fold increases in AUC predicted) and estimated the in vivo inactivation rate to be 0.00404 to 0.0318 h(-1) x ml/ng. In conclusion, FK1706 weakly or moderately inhibited the activity of CYP3A4/5 in vitro and vivo at the tested dose. The model developed here would be helpful in predicting drug-drug interactions and in the design of dose regimens that avoid drug-drug interactions.

Two Phase 1, Open-Label, Mass Balance Studies to Determine the Pharmacokinetics of 14 C-Labeled Isavuconazonium Sulfate in Healthy Male Volunteers.

Isavuconazonium sulfate is the water-soluble prodrug of the active triazole isavuconazole. Two phase 1 studies were conducted to identify the metabolic profile and mass balance of isavuconazole and BAL8728 (inactive cleavage product). Seven subjects in study 1 (isavuconazole mass balance) received a single oral dose of [cyano-14 C]isavuconazonium sulfate corresponding to 200 mg isavuconazole. Six subjects in study 2 (BAL8728 mass balance) received a single intravenous dose of [pyridinylmethyl-14 C]isavuconazonium sulfate corresponding to 75 mg BAL8728. Pharmacokinetic parameters of radioactivity in whole blood and plasma and of isavuconazole and BAL8728 in plasma were assessed. Radioactivity ratio of blood/plasma, percentage of dose, and cumulative percentage of radioactive dose recovered in urine and feces for isavuconazole and BAL8728 were assessed. Metabolic profiling was carried out by high-performance liquid chromatography and mass spectrometry. Mean plasma isavuconazole pharmacokinetic parameters included apparent clearance (2.3 ± 0.7 L/h), apparent volume of distribution (301.8 ± 105.7 L), and terminal elimination half-life (99.9 ± 44.6 hours). In study 1, isavuconazole-derived radioactivity was recovered approximately equally in urine and feces (46.1% and 45.5%, respectively). In study 2, BAL8728-derived radioactivity was predominantly recovered in urine (96.0%). Isavuconazole (study 1) and M4 (cleavage metabolite of BAL8728; study 2) were the predominant circulating components of radioactivity in plasma.

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 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 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.

Pharmacokinetics and Safety of Amenamevir in Healthy Subjects: Analysis of Four Randomized Phase 1 Studies.

INTRODUCTION: Amenamevir (ASP2151) is a nonnucleoside antiherpesvirus compound available for the treatment of varicella-zoster virus infections. In this article we summarize the findings of four phase 1 studies in healthy participants. METHODS: Four randomized phase 1 studies investigated the safety and pharmacokinetics of single and multiple doses of amenamevir, including the assessment of age group effect (nonelderly vs elderly), food effect, and the relative bioavailability of two formulations. Amenamevir was administered orally at various doses as a single dose (5-2400 mg) or daily (300 or 600 mg/day) for 7 days. RESULTS: Following single and multiple oral doses, amenamevir demonstrated a less than dose proportional increase in the pharmacokinetic parameters area under the plasma drug concentration versus time curve from time zero to infinity (AUCinf) and C max. After single and multiple oral 300-mg doses of amenamevir, no apparent differences in pharmacokinetics were observed between nonelderly and elderly participants. In contrast, with the amenamevir 600-mg dose both the area under the plasma drug concentration versus time curve from time zero to 24 h and C max were slightly increased and renal clearance was decreased in elderly participants. The pharmacokinetics of amenamevir was affected by food, with AUCinf increased by about 90%. In the bioavailability study, AUCinf and C max were slightly lower following tablet versus capsule administration (decreased by 14 and 12%, respectively), with relative bioavailability of 86%. The different amenamevir doses and formulations were safe and well tolerated; no deaths or serious adverse events were reported. CONCLUSION: Amenamevir had less than dose proportional pharmacokinetic characteristics. Age may have an influence on amenamevir pharmacokinetics; however, the effect was considered minimal. The pharmacokinetics of amenamevir were affected by food, with AUCinf almost doubling when amenamevir was administered with food. The concentration versus time profile of the tablet was slightly lower than that of the capsule; the relative bioavailability of the tablet versus the capsule was 86%. Amenamevir was safe and well tolerated in the dose range investigated. FUNDING: Astellas Pharma. TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT02852876 (15L-CL-002) and NCT02796118 (15L-CL-003).