First-in-Human, Phase 1, Randomized, Double-Blind, Placebo-Controlled Study of TNX-1500, an Fc-Modified anti-CD154 Monoclonal Antibody, Evaluating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single-Ascending Doses in Healthy Adults

Lemborexant, a dual orexin receptor antagonist, is approved for the treatment of insomnia and is under investigation for treating other sleep disorders. Here we summarize pharmacokinetic, pharmacodynamic, and safety data from 3 randomized, double‐blind, placebo‐controlled phase 1 studies: single ascending doses in healthy adults (Study 001; 1‐200 mg; N = 64), multiple ascending doses in healthy and elderly adults (Study 002; 2.5‐75 mg; N = 55), and multiple doses in healthy white and Japanese adults (Study 003; 2.5‐25 mg; N = 32). Lemborexant exposure increased with increasing dose. The time to maximum concentration ranged from approximately 1 to 3 hours for the 5‐ and 10‐mg doses. The mean effective half‐life was 17 hours for lemborexant 5 mg and 19 hours for lemborexant 10 mg. The plasma concentration at 9 hours postdose was 27% of the maximum concentration following multiple dosing with lemborexant 10 mg. There were no clinically relevant effects on next‐morning residual sleepiness (Karolinska Sleepiness Scale, Digital Symbol Substitution Test, Psychomotor Vigilance Test) for doses through 10 mg/day, indicating no effect of residual plasma concentrations on next‐day residual effects. Lemborexant was well tolerated across the doses tested. There were no clinically relevant effects of age, sex, or race on lemborexant pharmacokinetics, pharmacodynamics, or safety. These results suggest that lemborexant at doses through 25 mg provides an overall pharmacokinetic, pharmacodynamic, and safety profile suitable for obtaining the target pharmacologic effect supporting treatment of insomnia while minimizing residual effects during wake time.

This double-blind, first-in-human Phase I study evaluated pharmacokinetics, safety and tolerability of AL-794 (prodrug of ALS-033719), a potent endonuclease inhibitor of influenza A and B in healthy volunteers. Healthy adult volunteers were randomized to AL-794 (50-2,000 mg single ascending doses, fasting) or placebo (5 cohorts, n=6:2 AL-794: placebo/cohort) in part 1, and AL-794 (50-600 mg multiple ascending doses, twice-daily, fed or fasted) or placebo (3 cohorts, n=8:2 AL-794: placebo/cohort) for 7 days in part 2. In part 3, 8 healthy volunteers from part 1 received 450 mg AL-794 (n=6) or placebo (n=2) following a high-fat meal. All dosing was done with an oral suspension. Blood and urine samples for pharmacokinetics were collected at scheduled times and analysed for ALS-033719 and ALS-033927 (inactive glucuronide) plasma concentrations using LC-MS/MS. ALS-033719 plasma concentrations increased dose proportionately up to 150 mg but less than proportionately above 150 mg. Steady-state was generally achieved by the third dose. ALS-033719 exposure increased following administration with a standard meal (19%-33%) or high-fat meal (3-3.6-fold). ALS-033927 was the major metabolite observed. Renal elimination was negligible (0.2%). Seventeen AL-794-treated healthy volunteers reported ≥1 treatment-emergent adverse event (TEAE; part 1: n=6, 24%; part 2: n=11, 69%). The most common TEAEs were headache (part 1: n=3; part 2: n=5) and dizziness (part 1: n=2; part 2: n=6). AL-794 up to 200 mg twice daily achieved ALS-033719 exposures which are expected to be efficacious and were generally tolerated. Further studies are planned to characterize safety and antiviral activity.

Background Programmed cell death protein 1 (PD-1) is expressed on activated T cells and is a key co-inhibitory node in immune regulation. By targeting regulatory mechanisms to modulate immune cells driving disease, there is an opportunity to restore immune balance. Rosnilimab is a PD-1 agonist antibody designed to reduce T cell proliferation and inflammatory cytokine secretion and deplete PD-1high T follicular helper, T peripheral helper, and T effector cells. It is being studied for ulcerative colitis (UC), where PD-1+ T cells are prevalent in inflamed lamina propria (>40%) and the periphery. The primary objective of this healthy volunteer Phase 1 study was to assess the safety and tolerability of single ascending doses (SAD) and multiple ascending doses (MAD) of rosnilimab. Findings from pharmacokinetic (PK) and pharmacodynamic (PD) assessments are summarized. Methods This single-centre study included 14 cohorts in SAD and 3 cohorts in MAD. Each cohort had 8 participants (6 active, 2 placebo [PBO]). Cohorts were enrolled sequentially in each phase. Intravenous (IV) and subcutaneous (SC) administration were assessed in SAD; SC route was assessed in MAD. Results A total of 144 participants were enrolled; 90 to active SAD cohorts, 18 to active MAD cohorts, and 30 and 6 to SAD and MAD PBO cohorts, respectively. Rosnilimab was well tolerated with no dose-limiting toxicities or deaths. Two serious adverse events were reported in SAD (deemed unrelated to treatment) and 0 in MAD. PD-1 expressing cells were reduced by ~50% in both CD4+ and CD8+ subsets, in a dose-dependent manner and in correlation with full receptor occupancy (RO) through Day 30 in SAD. PD activity was rapid with sustained reduction in PD-1+ T cells, and ex-vivo stimulation resulted in reduced T cell functional activity. This reduction was maximized on PD-1high expressing T cells: ~90% reduction vs baseline. There was no significant impact on the overall total T cell or regulatory T (Treg) cell numbers, resulting in restoration of T cell composition to a less activated state and a positive shift in the Treg:Teff ratio. An antigen-specific functional T cell assay measuring ex vivo interferon-gamma release in response to antigen challenge was inhibited up to ~90% vs baseline and the response lasted for more than 30 days following a single dose. Rosnilimab had a favourable PK profile consistent with full RO, a 2-week half-life, and dose-proportional exposure in IV and SC dosing. Conclusion Rosnilimab demonstrated favourable safety, PK, and PD activity. The role of PD-1 in UC pathophysiology coupled with these results and translational data, demonstrate proof of mechanism and support progression into a Phase 2 study of rosnilimab in UC. (NCT06127043)

BackgroundLY3372689, an OGA enzyme inhibitor, is being developed as a potential treatment for tauopathies, including Alzheimer’s disease. OGA inhibition is proposed to delay the progression of tau‐related diseases by slowing the accumulation of hyper‐phosphorylated, insoluble tau filaments. We report the safety and pharmacokinetics (PK) of LY3372689 after single and multiple oral doses in healthy volunteers (HV).MethodThe single ascending dose (SAD) and multiple ascending dose (MAD) studies were single center, subject‐ and investigator‐blind, placebo‐controlled and randomized. In the SAD study [NCT03819270], 6 LY3372689 dose levels up to 16 mg and placebo were evaluated. In the MAD study [NCT04106206], LY3372689 (1, 3 and 7 mg) or placebo was given once daily (QD) for 14 days. Safety was assessed by adverse events (AE), safety laboratories, electrocardiograms, vital signs, physical exams, and neurological exams. Plasma pharmacokinetics (PK) was assessed in the SAD and MAD studies.ResultIn the SAD, 23 HV (15 males, 8 females; 22 – 63 years) participated, of which 18 HV completed. In the MAD, 40 HV (5 males, 35 females; 29 – 65 years) participated in the study, of which 39 HV completed. LY3372689 was generally well tolerated up to the highest dose in each study, and no serious AE were reported. In the SAD, 40 treatment‐emergent AEs (TEAEs) were reported, which were mostly mild in severity. The most common TEAEs were headache, nausea, pain in extremity, pain of skin, vessel puncture site pain, and limb discomfort. In the MAD, 42 TEAEs were reported, all of which were mild in severity. The most reported TEAE was headache. In both studies, there were no clinically significant changes in safety laboratories, including markers of inflammation, muscle injury, hormones and hepatoxicity. Following QD dosing of LY3372689, the tmax and t1/2 was about 1 hour and 6 hours, respectively, and LY3372689 exposure accumulation was minimal. Renal clearance was not a major contributor of LY3372689 elimination.ConclusionLY3372689 demonstrated an acceptable safety and PK profile following single and multiple doses of LY3372689 in HV. These results support investigation of LY3372689 in efficacy trials for tauopathies and help support dose selection for those trials.

ABSTRACTFosmanogepix (FMGX, APX001), a first-in-class, intravenous (i.v.) and oral (p.o.) antifungal prodrug candidate is currently in clinical development for the treatment of invasive fungal infections. Manogepix (MGX, APX001A), the active moiety of FMGX, interferes with cell wall synthesis by targeting fungal glycosylphosphatidylinositol-anchored cell wall transfer protein 1, thereby causing loss of cell viability. Data from two phase 1, placebo-controlled, single-ascending dose (SAD) and multiple-ascending dose (MAD) studies evaluating safety, tolerability, and pharmacokinetics of FMGX (doses up to 1,000 mg, i.v. and p.o.) are presented. Eligible participants were healthy adults (aged 18 to 55 years) randomized to receive either FMGX or placebo. Across both phase 1 studies, 151 of 154 participants (aged 23 to 35 years; FMGX: 116, placebo: 38) completed the study. Administration of FMGX i.v. demonstrated linear- and dose-proportional pharmacokinetics of MGX in terms of geometric mean maximum concentration of drug in serum (Cmax) (SAD: 0.16 to 12.0 μg/mL, dose: 10 to 1,000 mg; MAD: 0.67 to 15.4 μg/mL, dose: 50 to 600 mg) and area under the concentration-time curve (AUC) (SAD: 4.05 to 400, MAD: 6.39 to 245 μg · h/mL). With single and repeat p.o., dose-proportional increases in Cmax (SAD: 1.30 to 6.41 μg/mL, dose: 100 to 500 mg; MAD: 6.18 to 21.3 μg/mL, dose: 500 to 1,000 mg) and AUC (SAD: 87.5 to 205, MAD: 50.8 to 326 μg · h/mL) were also observed, with high oral bioavailability (90.6% to 101.2%). Administration of FMGX p.o. under post cibum conditions improved tolerability versus ante cibum conditions. No severe treatment-emergent adverse events (TEAEs), serious AEs, or withdrawals due to a drug-related TEAEs were reported with single or multiple i.v. and p.o. doses. Preclinical target exposures were achieved and were not accompanied by any serious/unexpected concerns with generally safe and well-tolerated dose regimens.

Introduction: Toxic gain-of-function Apolipoprotein L1 (APOL1) variants contribute to the development of proteinuric nephropathies collectively referred to as APOL1-mediated kidney disease (AMKD). Despite standard-of-care treatments, patients with AMKD experience accelerated progression to end-stage kidney disease. The identification of two APOL1 variants as the genetic cause of AMKD inspired development of inaxaplin, an inhibitor of APOL1 channel activity that reduces proteinuria in patients with AMKD. Methods: We conducted two phase 1 studies evaluating the safety, tolerability, and pharmacokinetics of single-ascending doses (SAD) and multiple-ascending doses (MAD) of inaxaplin in healthy participants. In the SAD cohorts, participants were randomized to receive inaxaplin as a single dose (range, 7.5 mg to 165 mg) or placebo. In the MAD cohorts, participants were randomized to receive multiple doses of inaxaplin (range, 15 to 120 mg daily) or placebo for 14 days. We assessed safety and tolerability based on adverse events (AEs), clinical laboratory values, electrocardiograms (ECGs), and vital signs. Results: A total of 178 participants were randomized in the SAD/MAD cohorts of both studies (mean age: 36.7 years; 94.9% male). The proportion of participants with any AEs was similar in the inaxaplin (24.6%) and placebo (22.7%) groups. All AEs were mild or moderate in severity; there were no serious AEs. Headache was the most common AE: 10.4% and 2.3% in the inaxaplin and placebo groups, respectively. There were no drug-related treatment discontinuations and no clinically relevant trends in laboratory values, ECGs, or vital signs. Discussion/Conclusion: Inaxaplin is safe and well tolerated at single doses up to 165 mg and multiple doses up to 120 mg daily for 14 days. These results are consistent with the favorable safety profile of inaxaplin in a completed phase 2a proof-of-concept study. Together, these findings support continued evaluation of inaxaplin in an ongoing phase 2/3 pivotal trial as a potential precision medicine for patients with AMKD.

Background and ObjectivesCerebral cavernous malformations (CCMs) are vascular lesions of the brain that can lead to hemorrhage, focal neurologic deficits, and seizures. Rho-associated kinase (ROCK) overactivation plays a critical role in the development of CCMs, and a novel, selective ROCK2 inhibitor, NRL-1049, mitigated lesion burden and bleeding in mouse models of CCM. This study examined the safety, tolerability, and pharmacokinetics of NRL-1049 in healthy volunteers.MethodsIn this first-in-human, randomized, double-blind, single-ascending dose study, participants received a single, oral dose of NRL-1049 (25, 75, 150, or 250 mg) or placebo in a fasted state (period 1). In period 2, participants received 150 mg NRL-1049 or placebo 30 min after a standardized high-fat, high-calorie meal. Blood samples for pharmacokinetic analysis were collected pre-dose and at post-dose time points from 5 min to 48 h. Treatment-emergent adverse events (TEAEs) were recorded and pharmacokinetic parameters determined, including maximum drug concentration (Cmax), time to Cmax (tmax), and area under the concentration-time curve (AUC) from time 0 to last quantifiable concentration (AUC0–t) and extrapolated to infinity (AUC0–∞).ResultsOf the 24 participants in period 1 who received NRL-1049 (fasted), 9 (37.5%) experienced ≥ 1 TEAE, with 8 (33.3%) reporting ≥ 1 treatment-related TEAE. TEAEs appeared to correlate with dose, and 150 mg was the maximum tolerated dose following single-dose administration in this study. The most common TEAEs (> 5%) were dizziness (16.7%), headache (8.3%), and syncope (8.3%). In period 2 (n = 10), four (40.0%) participants who received 150 mg NRL-1049 (fed) reported ≥ 1 TEAE, and three (30.0%) reported a treatment-related TEAE. There were no reports of serious TEAEs or discontinuations due to a TEAE. NRL-1049 was rapidly absorbed in the fasted state, with median tmax ranging from 0.50 to 0.75 h. Mean Cmax increased over the dose range of 25–250 mg (3.66–58.0 ng/mL). As NRL-1049 dose increased in a ratio of 1:3:6:10, mean Cmax similarly increased (1:5:10:16), while AUC0–t and AUC0–∞ increased in a greater-than-dose proportional manner (1:5:11:25 and 1:4:10:21, respectively; P < 0.001). In the fed state (150 mg NRL-1049), mean Cmax (18.5 ng/mL) was lower compared with the fasted state (34.9 ng/mL). For the active metabolite, NRL-2017, in the fasted state, median tmax was 0.88–1.63 h, and mean Cmax increased over the dose range (54.2–1520 ng/mL). Mean Cmax (1:6:14:28), AUC0–t (1:4:7:14), and AUC0–∞ (1:3:6:13) of NRL-2017 increased in a greater-than-dose proportional manner (P < 0.001). In the fed state, mean Cmax was lower compared with the fasted state.ConclusionsThe maximum tolerated dose of 150 mg NRL-1049 was associated with a favorable safety profile in healthy adult volunteers. Exposure of NRL-1049 and its active metabolite, NRL-2017, increased in a dose proportional or greater-than-dose proportional manner. These results support continued investigation and development of NRL-1049.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40263-025-01198-0.

This study aimed to evaluate the safety and tolerability, and characterize the pharmacokinetic profile, of zavegepant nasal spray in two phase 1 studies. Zavegepant is a high-affinity, selective, small-molecule calcitonin gene-related peptide receptor antagonist, approved as a nasal spray for the acute treatment of migraine in adults. Two single-site, phase 1, placebo-controlled, randomized, double-blind studies evaluated the safety, tolerability, and pharmacokinetic profile of single ascending doses (SAD) and multiple ascending doses (MAD) of zavegepant nasal spray in healthy adults. The SAD study was conducted from October 18, 2018, to March 15, 2019, and the MAD study from September 2, 2019, to December 14, 2019. Zavegepant SAD were 0.1-20 mg single sprays and 40 mg as two 20-mg sprays. Zavegepant MAD 5-20 mg single sprays once daily (QD) and three 40-mg QD regimens given as two 20-mg sprays were evaluated. In the SAD study, 72 participants were dosed in nine cohorts, and all participants completed the study. In the MAD study, 72 participants were dosed in six cohorts and 71 (99%) completed the study. In each study, zavegepant was rapidly absorbed, with a median time of maximum observed plasma concentration (Tmax) of 0.54 h after a single 10 mg spray (SAD study). Exposure increased with dose, with no evidence of accumulation after repeated QD dosing. In the SAD study, 14 (26%) zavegepant-treated and three (17%) placebo-treated participants reported at least one treatment-emergent adverse events (TEAE). In the MAD study, 42 (75%) zavegepant-treated participants and 10 (63%) placebo-treated participants reported at least one TEAE. In each study, most TEAEs were mild in severity and resolved spontaneously. There was no relevant effect on electrocardiographic parameters. No signal of drug-induced liver injury was identified. In healthy adults, zavegepant nasal spray was safe and well tolerated at single dose up to 40 mg and in multiple doses up to 40 mg QD. Zavegepant median Tmax was approximately 30 min after a single 10 mg dose nasal spray.

First-in-human single-dose study of nizubaglustat, a dual inhibitor of ceramide glucosyltransferase and non-lysosomal glucosylceramidase: Safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending and multiple doses in healthy adults

Study question Are increasing doses of single, subcutaneous (s.c.) injections of IGX12 safe for use in male and female healthy volunteers? Summary answer In a single ascending dose (SAD) study, IGX12 demonstrated a tolerability comparable to placebo in 16 male and 16 female healthy volunteers. What is known already Follicle stimulating hormone (FSH) regulates gametogenesis by acting on granulosa cells and Sertoli cells. IGX12 exerts its pharmacological action by binding to FSH and potentiating its activity, thereby improving gametogenesis. In vivo studies in female cynomolgus monkeys treated with IGX12 demonstrated a three-time higher ovarian stimulation output. In a model of male hypogonadotropic hypogonadism in rats, IGX12, added to hormonal treatment with FSH/LH and hCG, increased motile sperm count. In male hypogonadal mice, the addition of IGX12 to FSH/hCG treatment led to a ∼6-fold increase in motile sperm count. There were no obvious signs of toxicity in any species tested. Study design, size, duration This double-blind study followed recommendations for a First-in-Human study with sequential dose escalation after thorough safety review of each cohort, and a sentinel, staggered approach within cohorts, allowing investigation of the safety and tolerability of IGX12. No formal hypothesis was defined. Subjects received IGX12 or placebo and were followed in hospital for 6 days, followed by up to 11 outpatient visits. The study lasted 16 weeks from the start of treatment. Participants/materials, setting, methods 32 healthy volunteers (16 men and 16 women) were planned to be treated in 4 cohorts testing 5, 10, 20 and 40 µg/kg IGX12. Within each cohort, gender-wise randomization to IGX12 or placebo at a ratio of 3:1 was performed. To facilitate treatment start in female participants, contraception was used to synchronize menstrual cycles. Main results and the role of chance 32 participants aged from 21 to 49 years were treated and completed the study. Exposure in terms of Cmax and AUC0-tlast increased with increasing doses. IGX12 was slowly absorbed with a median tmax of 12 to 16 days and slowly eliminated with a half-life of approximately 43 days. There was limited occurrence of anti-drug antibodies, all with low titers, and no observable impact on IGX12 pharmacokinetics. In women, no negative effects on ovarian stimulation or hormone levels were observed and increase in ovarian volume and endometrial thickness were within expected ranges. In men, no effects on testis morphology or hormones were observed. Sperm counts showed a high intraindividual variability, but values were always within normal ranges. Overall, 24 (75%) participants reported a treatment-emergent adverse event (TEAE), with 12 (37.5%) participants reporting TEAEs considered related to IGX12. The frequency of TEAEs was similar across active and placebo. No severe TEAEs, TEAEs leading to discontinuation or serious TEAEs were reported. Limitations, reasons for caution The study was designed to assess the safety of IGX12. This clean safety profile is to be confirmed in the multiple ascending dose study that is still ongoing in healthy male volunteers. Wider implications of the findings IGX12 is an FSH-potentiating monoclonal antibody that has been shown to have the potential to change the treatment paradigm for infertility. Its long half-life may allow bi-weekly or monthly dosing. The results of this study will allow further testing and setting up of Phase 2 trials. Trial registration number Yes

Proteinuria associated with podocyte effacement is a hallmark of focal segmental glomerulosclerosis (FSGS). Preclinical studies implicated ROBO2/SLIT2 signaling in the regulation of podocyte adhesion, and inhibition of this pathway is a novel target to slow FSGS disease progression. This first‐in‐human dose‐escalation study evaluated the safety, tolerability, pharmacokinetics, and immunogenicity of PF‐06730512, an Fc fusion protein that targets the ROBO2/SLIT2 pathway, in healthy adults. In this Phase 1, double‐blind, sponsor‐open study, single ascending dose (SAD) cohorts were randomized to receive up to 1000 mg or placebo intravenously (IV); multiple ascending dose (MAD) cohorts were randomized to receive up to 400 mg subcutaneous (SC) doses, 1000 mg IV dose, or matching placebo. Safety evaluations were performed up to 71 (SAD) and 113 (MAD) days after dosing; blood samples were collected to measure serum PF‐06730512 concentrations and antidrug antibodies (ADA) to PF‐06730512. Seventy‐nine participants (SAD, 47; MAD, 32) were enrolled. There were 108 mild (SAD, 46; MAD, 62) and 21 moderate (SAD, 13; MAD, 8) treatment‐emergent adverse events (TEAEs); no deaths, treatment‐related serious AEs, severe TEAEs, or infusion reactions were reported. PF‐06730512 exposure generally increased in an approximately dose‐proportional manner; mean t 1/2 ranged from 12–15 days across 50–1000 mg doses. Immunogenicity incidence was low (SAD, 0 ADA+; MAD, 2 ADA+). In conclusion, single IV doses of PF‐06730512 up to 1000 mg and multiple IV and SC dosing up to 1000 and 400 mg, respectively, were safe and well tolerated in healthy participants. Further trials in patients with FSGS are warranted. Clinical trial registration: Clinicaltrials.gov: NCT03146065.

The risk of vitamin D insufficiency is increased in persons having limited sunlight exposure and dietary vitamin D. Supplementation compliance might be improved with larger doses taken less often, but this may increase the potential for side effects. The objective of the present study was to determine whether a weekly or weekly/monthly regimen of vitamin D supplementation is as effective as daily supplementation without increasing the risk of side effects. Participants were forty-eight healthy adults who were randomly assigned for 3 months to placebo or one of three supplementation regimens: 50 μg/d (2000 IU/d, analysed dose 70 μg/d), 250 μg/week (10 000 IU/week, analysed dose 331 μg/week) or 1250 μg/week (50 000 IU/week, analysed dose 1544 μg/week) for 4 weeks and then 1250 μg/ month for 2 months. Daily and weekly doses were equally effective at increasing serum 25-hydroxyvitamin D, which was significantly greater than baseline in all the supplemented groups after 30 d of treatment. Subjects in the 1250 μg treatment group, who had a BMI >26 kg/m2, had a steady increase in urinary Ca in the first 3 weeks of supplementation, and, overall, the relative risk of hypercalciuria was higher in the 1250 μg group than in the placebo group (P=0·01). Although vitamin D supplementation remains a controversial issue, these data document that supplementing with ≤ 250 mg/week (≤ 10 000 IU/week) can improve or maintain vitamin D status in healthy populations without the risk of hypercalciuria, but 24 h urinary Ca excretion should be evaluated in healthy persons receiving vitamin D3 supplementation in weekly single doses of 1250 μg (50 000 IU).

FRI0230 Assessment of Safety, Pharmacokinetics and Pharmacodynamics of A Novel anti-CD40 Monoclonal antibody, CFZ533, in Healthy Volunteers and in Rheumatoid Arthritis Patients

First-in-human clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody.

Micafungin is a selective inhibitor of the synthesis of fungal 1,3-β-d-glucan, an essential component of the fungal cell wall. It is available as a powder for infusion only and is registered for the treatment of invasive and esophageal candidiasis in addition to prophylaxis of Candida infections in both adults and children. Average exposure after a single intravenous 100 mg dose in healthy adults is 133 mg h/L. Both exposure and maximum plasma concentration show linear dose proportional pharmacokinetics (PK) over a 0.15–8 mg/kg dose range. In healthy adults, the clearance (CL) is 10.4 mL/h/kg and volume of distribution is 0.2 L/kg; both are independent of the dose. Micafungin is metabolized by arylsulfatase, catechol-O-methyltransferase, and several cytochrome P450 (CYP) isoenzymes (3A4, 1A2, 2B6 and 2C), but no dose adjustments are necessary in patients with (severe) hepatic dysfunction. Exposure to micafungin is lower in hematology patients, and is even further lowered in critically ill patients (including burn patients) compared with healthy volunteers, which might have consequences for treatment efficacy. In children, an increased CL has been reported: 40–80 mL/h/kg in premature neonates and 20 mL/h/kg in children >4 months of age. Therefore, relatively higher doses of 4–10 mg/kg in premature neonates and 2–4 mg/kg in children with invasive candidiasis are used. However, these higher CLs may also be explained by the eightfold higher free fraction of unbound micafungin in premature neonates, meaning that an augmented dose might not be required.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-017-0578-5) contains supplementary material, which is available to authorized users.