Donna Kowalski

Proarrhythmic Safety of Repeat Doses of Mirabegron in Healthy Subjects: A Randomized, Double-Blind, Placebo-, and Active-Controlled Thorough QT Study

Potential effects of the selective β3‐adrenoceptor agonist mirabegron on cardiac repolarization were studied in healthy subjects. The four‐arm, parallel, two‐way crossover study was double‐blind and placebo‐ and active (moxifloxacin)‐controlled. After 2 baseline ECG days, subjects were randomized to one of eight treatment sequences (22 females and 22 males per sequence) of placebo crossed over with once‐daily (10 days) 50, 100, or 200 mg mirabegron or a single 400‐mg moxifloxacin dose on day 10. In each period, continuous ECGs were recorded at two baselines and on the last drug administration day. The lower one‐sided 95% confidence interval for moxifloxacin effect on QTcI was >5 ms, demonstrating assay sensitivity. According to ICH E14 criteria, mirabegron did not cause QTcI prolongation at the 50‐mg therapeutic and 100‐mg supratherapeutic doses in either sex. Mirabegron prolonged QTcI interval at the 200‐mg supratherapeutic dose (upper one‐sided 95% CI >10 ms) in females, but not in males.

A phase 1, randomized ascending single-dose study of antagonist anti-human CD40 ASKP1240 in healthy subjects.

This first‐in‐human, phase I study evaluated the safety, tolerability, pharmacokinetic and pharmacodynamic profile of ASKP1240 in healthy subjects. Twelve sequential groups (each 6 active and 3 placebo) were randomly assigned to placebo or single ascending doses of intravenous ASKP1240 (0.00003–10 mg/kg). ASKP1240 exhibited nonlinear pharmacokinetics, with mean maximal serum concentrations and area under the serum concentration–time curves ranging from 0.7 to 251.6 μg/mL and 6.5 to 55409.6 h·μg/mL following doses 0.1 mg/kg–10 mg/kg, respectively. CD40 receptor occupancy by ASKP1240, which was dose‐dependent, reached a maximum at doses above 0.01 mg/kg. ASKP1240 was well tolerated, with no evidence of cytokine release syndrome or thromboembolic events. Treatment emergent antibodies to ASKP1240 were detected in 5/70 (7.1%) ASKP1240 recipients. In conclusion, antagonism of the CD40/CD154 interaction with ASKP1240 was safe and well tolerated at the doses tested.

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.

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.

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.

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.

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.

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.

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.