James Keirns

Safety, Tolerability, and Pharmacokinetics of Micafungin (FK463) in Febrile Neutropenic Pediatric Patients

ABSTRACT Micafungin (FK463) is a new parenteral echinocandin. A multicenter, phase I, open-label, sequential-group dose escalation study was conducted to assess the safety, tolerability, and pharmacokinetics of micafungin in neutropenic pediatric patients. A total of 77 patients stratified by age (2 to 12 and 13 to 17 years) received micafungin. Therapy was initiated at 0.5 mg/kg per day and escalated to higher dose levels of 1.0, 1.5, 2.0, 3.0, and 4.0 mg/kg per day. Micafungin was administered within 24 h of initiating broad-spectrum antibacterial antibiotics for the new onset of fever and neutropenia. The most common overall adverse events in the study population were diarrhea (19.5%), epistaxis (18.2%), abdominal pain (16.9%), and headache (16.9%). Nine patients (12%) experienced adverse events considered by the investigator to be possibly related to the study drug. The most common related events were diarrhea, vomiting, and headache, all occurring in two patients each. There was no evidence of a dose-limiting toxicity as defined within the prespecified criteria of this clinical protocol. There was one death during the study due to septic shock. The pharmacokinetic profiles for micafungin over the 0.5- to 4.0-mg/kg dose range demonstrated dose linearity. Clearance, volume of distribution, and half-life remained relatively constant over the dose range and did not change with repeated administration. The overall plasma pharmacokinetic profile was similar to that observed in adults. However, there was an inverse relation between age and clearance. For patients 2 to 8 years old, clearance was approximately 1.35 times that of patients ≥9 years of age. In summary, micafungin over a dosage range between 0.5 and 4.0 mg/kg/day in 77 febrile neutropenic pediatric patients displayed linear pharmacokinetics and increased clearance as a function of decreasing age.

Pharmacokinetics of Micafungin in Healthy Volunteers, Volunteers With Moderate Liver Disease, and Volunteers With Renal Dysfunction

Micafungin is an antifungal agent metabolized by arylsulfatase with secondary metabolism by catechol‐O‐methyltransferase. The objectives of this study were to estimate the pharmacokinetic parameters and plasma protein binding of micafungin in volunteers with moderate hepatic dysfunction (n = 8), volunteers with creatinine clearance <30 mL/min (n = 9), and matched controls (n = 8 and n = 9, respectively). Single‐dose micafungin pharmacokinetics were estimated using noncompartmental techniques. There was a statistically lower area under the observed micafungin concentration‐time curve (AUC) from time 0 to infinity for subjects with moderate hepatic dysfunction as compared to control subjects (97.5 ± 19 μg•h/mL vs 125.9 ± 26.4 μg•h/mL, P = .03), although there was no difference in micafungin weight‐adjusted clearance (10.9 ± 1.7 mL/h/kg vs 9.8 ± 1.8 mL/h/kg, P = .2). The difference in area under the concentration‐time curve may be explained by the differences in body weight between subjects and controls. Renal dysfunction did not alter micafungin pharmacokinetics.

The pharmacokinetics and safety of micafungin, a novel echinocandin, in premature infants

Background: Candidal fungal infection rates in neonates are increasing and are a significant cause of mortality, especially in low birth weight infants. Micafungin is an echinocandin that works by inhibiting 1,3-β-D-glucan synthase, an enzyme responsible for fungal cell wall synthesis. The objective of this study was to determine the safety and pharmacokinetics of micafungin in premature infants. Methods: This was a phase I, single-dose, multicenter, open-label, sequential-dose trial of intravenous micafungin investigating 3 doses (0.75 mg/kg, 1.5 mg/kg and 3.0 mg/kg) in 18 premature infants weighing >1000 g (n = 6 in each dosage group). A further 5 infants (500–1000 g) were enrolled in the 0.75 mg/kg dosage group only. Results: The mean ± standard deviation gestational age in the >1000 g dosage group was 26.4 ± 2.4 weeks and, on entry, patients had one or more of a variety of underlying conditions, including sepsis, pneumonia and other infections caused by Candida or other species. Micafungin pharmacokinetics in preterm infants appears linear. However, premature infants >1000 g on average displayed a shorter half-life (8 hours) and a more rapid rate of clearance (approximately 39 mL/h per kg) compared with published data in older children and adults. All doses of micafungin were well tolerated and no serious drug-related adverse events were observed. Conclusions: Single doses of micafungin, ranging up to 3.0 mg/kg, appear well tolerated in premature infants weighing >1000 g. The drugs elimination half-life and total plasma clearance in preterm infants appear dissimilar to published values for these parameters in older children and adults. The reason(s) for this apparent difference remain to be investigated.

Pharmacokinetic and Maximum Tolerated Dose Study of Micafungin in Combination with Fluconazole versus Fluconazole Alone for Prophylaxis of Fungal Infections in Adult Patients Undergoing a Bone Marrow or Peripheral Stem Cell Transplant

ABSTRACT In this dose escalation study, 74 adult cancer patients undergoing bone marrow or peripheral blood stem cell transplantation received fluconazole (400 mg/day) and either normal saline (control) (12 subjects) or micafungin (12.5 to 200 mg/day) (62 subjects) for up to 4 weeks. The maximum tolerated dose (MTD) of micafungin was not reached, based on the development of Southwest Oncology Group criteria for grade 3 toxicity; drug-related toxicities were rare. Commonly occurring adverse events considered related to micafungin were headache (6.8%), arthralgia (6.8%), hypophosphatemia (4.1%), insomnia (4.1%), maculopapular rash (4.1%), and rash (4.1%). Pharmacokinetic profiles for micafungin on days 1 and 7 were similar. The mean half-life was approximately 13 h, with little variance after repeated or increasing doses. Mean maximum concentrations of the drug in serum and areas under the concentration-time curve from 0 to 24 h were approximately proportional to dose. There was no clinical or kinetic evidence of interaction between micafungin and fluconazole. Five of 12 patients (42%) in the control group and 14 of 62 (23%) in the micafungin-plus-fluconazole groups had a suspected fungal infection during treatment which resulted in empirical treatment with amphotericin B. The combination of micafungin and fluconazole was found to be safe in this high-risk patient population. The MTD of micafungin was not reached even at doses up to 200 mg/day for 4 weeks. The pharmacokinetic profile of micafungin in adult cancer patients with blood or marrow transplants is consistent with the profile in healthy volunteers, and the area under the curve is proportional to dose.

The pharmacokinetics and pharmacodynamics of micafungin in experimental hematogenous Candida meningoencephalitis: Implications for echinocandin therapy in neonates

BACKGROUND Hematogenous Candida meningoencephalitis (HCME) is a relatively frequent manifestation of disseminated candidiasis in neonates and is associated with significant mortality and neurodevelopmental abnormalities. The outcome after antifungal therapy is often suboptimal, with few therapeutic options. Limited clinical data suggest that echinocandins may have role to play in the treatment of HCME. METHODS We studied the pharmacokinetics and pharmacodynamics of micafungin in a rabbit model of neonatal HCME and bridged the results to neonates by use of population pharmacokinetics and Monte Carlo simulation. RESULTS Micafungin exhibited linear plasma pharmacokinetics in the range of 0.25-16 mg/kg. Micafungin penetrated most compartments of the central nervous system (CNS), but only with doses >2 mg/kg. Micafungin was not reliably found in cerebrospinal fluid. With few exceptions, drug penetration into the various CNS subcompartments was not statistically different between infected and noninfected rabbits. A dose-microbiological response relationship was apparent in the brain, and near-maximal effect was apparent with doses of 8 mg/kg. Monte Carlo simulations revealed that near-maximal antifungal effect was attained at human neonatal doses of 12-15 mg/kg. CONCLUSIONS These results provide a foundation for clinical trials of micafungin in neonates with HCME and a model for antimicrobial bridging studies from bench to bedside in pediatric patients.

Population Pharmacokinetics of Micafungin in Pediatric Patients and Implications for Antifungal Dosing

ABSTRACT The echinocandins potentially have an important role in treatment of infections caused by Candida spp. and Aspergillus spp. in immunocompromised children. However, there are no population pharmacokinetic models of the echinocandins for pediatric patients. The safety and descriptive pharmacokinetics of micafungin in children were recently reported. However, a population pharmacokinetic model in children is needed in order to accurately determine the dosage of micafungin that produces an equivalent magnitude of drug exposure to that observed in adults. In order to explore the effect of weight on micafungin pharmacokinetics, a standard two-compartment pharmacokinetic model, a linear model, and an allometric power model were developed. For all three models, the fit to the data was excellent, with comparable measures of precision and bias. However, the superior log-likelihood value of the allometric power model suggested that it best reflected the data and was therefore chosen for a more detailed analysis of the magnitude and pattern of drug exposure which develop following the administration of micafungin. The allometric power model suggested that clearance in smaller children is higher than that predicted on the basis of weight alone. Consequently, a degree of dosage increase is required in smaller children to ensure comparable levels of drug exposure to those observed in larger children and adults. The allometric power model developed in this study enables identification of pediatric dosage regimens of micafungin which, based upon Monte Carlo simulations, result in equivalent drug exposures to those observed in adults, for which antifungal efficacy has been established.

Concomitant cyclosporine and micafungin pharmacokinetics in healthy volunteers.

Cyclosporine is a marketed immunosuppressive agent and a known substrate for CYP3A. Micafungin is an antifungal agent and a mild inhibitor of CYP3A‐mediated metabolism in vitro. The objectives of this study were to evaluate the pharmacokinetics of cyclosporine and micafungin before and with concomitant administration. The pharmacokinetics of single‐dose oral cyclosporine (5 mg/kg) were estimated on days 1, 9, and 15 (n = 27). Subjects received micafungin (100 mg/d over 1 hour) on days 7, 9, and 11 through 15. Micafungin pharmacokinetics were estimated on days 7, 9, and 15. Mean apparent oral cyclosporine clearances were estimated to be 645 ± 236 mL/h/kg, 546 ± 101 mL/h/kg (P = .01), and 540 ± 104 mL/h/kg (P = .02) for days 1, 9, and 15, respectively. Micafungin appears to be a mild inhibitor of cyclosporine metabolism.

Results From the IQ‐CSRC Prospective Study Support Replacement of the Thorough QT Study by QT Assessment in the Early Clinical Phase

The QT effects of five “QT‐positive” and one negative drug were tested to evaluate whether exposure–response analysis can detect QT effects in a small study with healthy subjects. Each drug was given to nine subjects (six for placebo) in two dose levels; positive drugs were chosen to cause 10 to 12 ms and 15 to 20 ms QTcF prolongation. The slope of the concentration/ΔQTc effect was significantly positive for ondansetron, quinine, dolasetron, moxifloxacin, and dofetilide. For the lower dose, an effect above 10 ms could not be excluded, i.e., the upper bound of the confidence interval for the predicted mean ΔΔQTcF effect was above 10 ms. For the negative drug, levocetirizine, a ΔΔQTcF effect above 10 ms was excluded at 6‐fold the therapeutic dose. The study provides evidence that robust QT assessment in early‐phase clinical studies can replace the thorough QT study.

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.

Concomitant Tacrolimus and Micafungin Pharmacokinetics in Healthy Volunteers

Tacrolimus is an approved immunosuppressive agent and a known substrate for CYP3A. Micafungin is an echinocandin antifungal agent and a mild inhibitor of CYP3A metabolism in vitro. The objectives of this study were to evaluate the pharmacokinetics of tacrolimus (5 mg oral) and micafungin (100 mg intravenous) alone and with concomitant administration (n = 26). Tacrolimus area under the concentration‐time curve was 298 ± 135 μg•h/L when tacrolimus was administered alone, 305 ± 129 μg•h/L (P = .8; confidence interval 89%, 118%) when tacrolimus was given with single‐dose micafungin, and 282 ± 138 μg•h/L (P = .4; confidence interval 82%, 107%) when tacrolimus was given with steady‐state micafungin. Despite the mild inhibition of CYP3A in vitro by micafungin, there does not appear to be a drug interaction with tacrolimus and micafungin either with single‐dose or steady‐state micafungin administration.