Multiple-ascending Oral Doses Research Articles

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Muscarinic M3 Receptor-Positive Allosteric Modulator ASP8302 Following Single and Multiple Ascending Oral Doses in Healthy Volunteers.

ASP8302 is an orally administered positive allosteric modulator of the muscarinic M3 receptor. Two Phase 1 studies were conducted, a first-in-human study in Europe and a Japanese phase 1 study. Both were randomized, participant- and investigator-blinded, placebo-controlled, single and multiple ascending oral doses, parallel group, clinical studies in healthy volunteers. Both studies evaluated safety and pharmacokinetics and also included salivary secretion and pupil diameter as pharmacodynamic assessments. There were no deaths, serious adverse events, or treatment-emergent adverse events reported leading to study discontinuation. There were no clinically relevant findings in any of the laboratory, vital signs, electrocardiogram assessments, or photosensitivity testing following multiple administration of up to 150 mg or up to 140 mg once daily for 14 days in the European first-in-human and Japanese Phase 1 study, respectively. The pharmacokinetics of ASP8302 were approximately linear over the dose range studied. There was no evidence of drug accumulation upon repeated dosing. In both studies, ASP8302 showed a dose-dependent pharmacodynamic effect on saliva production at doses from 100 mg onward, which was maintained during repeated dosing. No effect was observed on pupil diameter. These data supported progression of ASP8302 into Phase 2 clinical trials for further clinical development.

Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Oral Doses of Youkenafil Hydrochloride, a Phosphodiesterase Type 5 Inhibitor, in Healthy Chinese Male Volunteers.

Youkenafil hydrochloride is a novel selective phosphodiesterase type 5 inhibitor for the treatment of erectile dysfunction. Its safety, tolerability, and pharmacokinetics were evaluated in healthy Chinese male volunteers. In addition, this study explored the effect of food on the pharmacokinetic parameters of youkenafil hydrochloride. The study was divided into 3 trials: a single ascending dose (25, 50, 100, 150, or 200 mg youkenafil), multiple dose (50, 100, or 150 mg youkenafil once daily for 7 consecutive days), and food effect (50 mg youkenafil single dose). The overall tolerability of youkenafil was good. Youkenafil was rapidly absorbed after a single oral dose. Food intake impeded absorption efficiency but had no significant effect on area under the plasma concentration-time curve values. The mean accumulation ratio in area under the plasma concentration-time curve and maximum plasma concentration ranged from 1.3 to 1.6 and from 1.2 to 1.4 after once-daily dosing. There was no apparent accumulation following consecutive administration for 7 days. Less than 1% of the dose was found in urine as the intact drug for all dose groups. Single-dose youkenafil up to 200 mg and multiple doses up to 150 mg were generally safe and well tolerated.

Phase 1 Single and Multiple Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AG-946 in Healthy Volunteers

Background: Glycolysis is the primary source of ATP in red blood cells (RBCs), which is critical for maintaining RBC health. Pyruvate kinase red cell isoform (PKR) catalyzes the final step of glycolysis to generate ATP. Enhancing ATP production via PKR activation is under investigation as a potential therapeutic approach in hemolytic anemias. Increased levels of the glycolytic metabolite 2,3-diphosphoglycerate (2,3-DPG) in sickle cell disease (SCD) decreases hemoglobin oxygen affinity and results in increased RBC sickling. PKR activation has been shown to reduce 2,3-DPG. In previous clinical studies in pyruvate kinase deficiency, thalassemia and SCD, treatment with mitapivat, a PKR activator, led to improvements in hemoglobin and markers of hemolysis.AG-946 is an investigational, next-generation, oral small molecule activator of wild-type and mutant PKR isoforms, with high potency. Modelling from preclinical studies suggest that AG-946 is likely to have a pharmacokinetic (PK) profile that allows for once daily (QD) dosing and long duration of pharmacodynamic (PD) effects in humans. Here we report preliminary blinded results from an ongoing study assessing the safety, tolerability, PK and PD of AG-946 in healthy volunteers (NCT04536792).Methods: In this phase 1, randomized, double-blind, placebo (P)-controlled study, single ascending oral doses (SAD) or multiple ascending oral doses (MAD) of AG-946 were administered under fasting conditions to healthy men and women (18-55 years of age) in sequential cohorts. In SAD (4 cohorts of 8 subjects each) and in MAD (2 cohorts of 8 subjects each) subjects were planned to be randomized to receive either AG-946 (n=6) or P (n=2). The dose levels studied so far are 1, 3, 10, and 30 mg in SAD and 1 mg QD and 2 mg QD for 14 days in MAD. Safety assessments included vital signs, physical exams, electrocardiograms, clinical laboratory parameters and adverse events (AEs). Serial blood samples were drawn for PK and PD (2,3-DPG; ATP) assessments at regular intervals throughout the study period.Results: As of June 02, 2021, 39 (median age 33 years; n = 33 male) subjects in SAD and 17 (median age 36 years; all male) subjects in MAD received AG-946 or P. There were 6 (SAD, n = 5; MAD, n = 1) early discontinuations; all were unrelated to study treatment. In SAD, 4/39 (10.3%) subjects experienced ≥ 1 treatment-emergent AE (TEAE); all TEAEs were assessed as mild (Grade [Gr] 1). In MAD 4/17 (23.5%) subjects experienced ≥ 1 TEAE; the majority of the TEAEs were mild (Gr 1), with 1 subject experiencing a serious AE (Gr 2) of exercise-induced rhabdomyolysis 14 days after last dose, considered unrelated to study treatment. All other AEs in SAD and MAD were also considered unrelated to study treatment.In both SAD and MAD, AG-946 exhibited rapid absorption with median T max (time to maximum concentration) ranging from 0.5 to 1 hour. Following SAD, dose-normalized AG-946 exposures (AUC and C max [area under the curve and maximum concentration observed]) increased with increasing AG-946 doses, suggesting a greater than dose proportional increase in exposure over the tested dose range. Following MAD, AG-946 exposures were higher on Day 14 compared with Day 1, with mean accumulation ratios based on AUC of 3.6 at 1 mg QD and 3.3 at 2 mg QD, and mean accumulation ratios based on C max of 1.95 at 1 mg QD and 1.6 at 2 mg QD.In both SAD and MAD, an increase in AG-946 dose was associated with a decrease in 2,3-DPG concentrations (Figure 1), and an increase in ATP concentrations (Figure 2). The PD changes were sustained up to 168 hours after a single dose and > 7 days after the last day of multiple QD dosing, consistent with the slow off-rate from PKR.As expected, no clinically significant changes in Hb have been observed in the SAD or MAD cohorts, to date.Conclusions: AG-946, a highly potent PKR activator, was well tolerated in healthy volunteers following single dose administrations up to 30 mg and multiple 14-day dosing with 1 mg QD and 2 mg QD. The PK profile of AG-946 supports QD dosing, and is accompanied by sustained dose-dependent increases in ATP and decreases in 2,3-DPG, consistent with activation of the glycolytic pathway. Enrollment into additional SAD and MAD cohorts is ongoing and will be followed by an open-label phase in subjects with SCD. [Display omitted] DisclosuresIyer: Novartis: Current equity holder in publicly-traded company; Agios Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Ronseaux: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Gamache: Agios Pharmaceuticals: Current Employment. Callaghan: Agios Pharmaceuticals: Current Employment.

Tolerability, safety, pharmacokinetics and pharmacodynamics of SHR0534, a potent G protein-coupled receptor 40 (GPR40) agonist, at single- and multiple-ascending oral doses in healthy Chinese subjects

SHR0534 is being developed for type-2 diabetes mellitus. Herein the tolerability, safety, pharmacokinetics and pharmacodynamics of SHR0534 in healthy Chinese subjects were assessed in a phase-I, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose study. Forty subjects were randomized 4:1 to receive SHR0534 at the dose of 10, 25, 50 or 100 mg, or placebo, and another eleven subjects were allocated to either the 5 mg group or the placebo group at an 8:3 ratio. All subjects received a single dose on day 1, followed by a 9-day washout and once-daily administrations for 14 consecutive days. Serial samples were collected, and vital signs, electrocardiograms, laboratory tests, urinalysis and adverse events (AEs) were recorded. All doses of SHR0534 were safe and well tolerated with infrequent, generally mild-to-moderate AEs and no serious AEs in the study. SHR0534 was absorbed with a T max of approximately 4 hours, and systemic exposure increased with dose. Accumulation was minimal (2- to 3-fold) and steady state was reached after seven days of dosing. For pharmacodynamics, no significant hypoglycaemic effects were seen in healthy adults. Good pharmacokinetics and safety were demonstrated but no obvious effect was found.

Multiple-dose clinical pharmacology of the selective orexin-1 receptor antagonist ACT-539313

AimsCompounds that selectively target orexin-1 receptors may be beneficial for the treatment of various disorders. The role of selective orexin-1 receptor antagonists (1-SORAs) in addictive behavior and stress/anxiety-related disturbances has been demonstrated in animals. ACT-539313, an orally active, potent 1-SORA, has been assessed in a clinical single-ascending dose study and exhibited good safety and tolerability. In the two reported studies on ACT-539313, multiple-dose pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability were investigated and in a proof-of-mechanism study a CO2 challenge was applied as pharmacological model for induction of anxiety and panic symptoms (sequential inhalation of air, 7.5% CO2, and 35% CO2). MethodsTwo double-blind, placebo-controlled, randomized, multiple-dose studies included 58 healthy male and female subjects. In Study 1, multiple-ascending oral doses of 30, 100, and 200 mg twice daily (b.i.d.) ACT-539313 were investigated in 3 dose groups of 8 or 12 subjects (of whom 2 received placebo per dose group). Study 2 was conducted as a randomized two-way crossover design, enrolling 21 male and 9 female subjects who received 200 mg ACT-539313 or matching placebo b.i.d. for 2.5 days followed by a CO2 challenge, with a washout period in between. PK, PD (objective and subjective measures of sedation, alertness, effects on central nervous system (CNS), and anxiety/panic symptoms), safety, and tolerability were assessed. ResultsAt steady state, ACT-539313 was rapidly absorbed with a median time to maximum plasma concentration of 1.8–2.3 h and eliminated with a mean half-life of 3.8–6.5 h. Overall exposure increased dose-proportionally. In Study 1, PD effects confirmed activity of ACT-539313 on the CNS, without consistent or marked effects of sedation, reduced alertness or visuo-motor impairment. In the CO2 challenge, cortisol concentrations were lower during initial air inhalation after treatment with ACT-539313 compared to placebo, while no difference was detected after CO2 inhalation. Trends for lower scores in subjective anxiety assessments were observed for ACT-539313. Besides reports of stress related to the challenge, the most frequently reported adverse events were somnolence and headache. No clinically relevant effects in other safety assessments were observed. ConclusionsMultiple-dose administration of ACT-539313 was safe and well tolerated up to multiple doses of 200 mg b.i.d. The drug's PK properties as well as the pattern of a decrease in stress-related symptoms after the CO2 challenge support further investigations of ACT-539313.

Safety, Tolerability and Pharmacokinetics of Vidofludimus calcium (IMU-838) After Single and Multiple Ascending Oral Doses in Healthy Male Subjects

Background and ObjectiveVidofludimus is a potent and selective inhibitor of human mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). The clinical efficacy and safety profile of vidofludimus has been analyzed in patients suffering from rheumatoid arthritis and Crohn’s disease and ulcerative colitis. In previous sudies, hematuria at higher doses occurred in close temporal relationship to vidofludimus administration and appeared to be dose related. The present report describes the results from two phase 1 studies conducted in healthy male subjects to investigate the safety, tolerability and pharmacokinetics after single and multiple ascending (SAD and MAD) oral doses of IMU-838 (vidofludimus calcium, tablets containing a specific polymorph). The effect of food on the pharmacokinetics of IMU-838 was also assessed in the SAD study.MethodsIn the SAD study, 12 subjects received single doses of IMU-838 under fasting (10–40 mg) or fed (10 mg) condition in an open-label, partial parallel group design. In the MAD study, 52 subjects received multiple doses of IMU-838 (30–50 mg) in a double-blind, placebo-controlled, parallel group design.ResultsIMU-838 showed dose-proportional pharmacokinetics after single and multiple oral dosing in both SAD and MAD studies. IMU-838 was well absorbed after single daily doses. Food did not impact the pharmacokinetics of IMU-838. The accumulation factor for multiple daily dosing was approximately 2. Steady-state concentrations were reached within about 6–8 days for 30–50 mg groups. The geometric mean plasma half-life of IMU-838 at steady state was approximately 30 h, which supports its use for once-daily dosing regimen. Single and multiple oral doses of IMU-838 were safe and well tolerated.ConclusionOverall, oral IMU-838 was generally well tolerated in SAD and MAD studies in healthy subjects over a wide dose range of 10–50 mg. IMU-838 was well absorbed after single daily doses. IMU-838 showed dose proportional pharmacokinetics after single and multiple oral dosing.Electronic supplementary materialThe online version of this article (10.1007/s13318-020-00623-7) contains supplementary material, which is available to authorized users.

Safety, tolerability and pharmacokinetics of oral nafithromycin (WCK4873) after single or multiple doses and effects of food on single-dose bioavailability in healthy adult subjects.

Nafithromycin (WCK 4873), a novel lactone-ketolide, was administered to healthy adult subjects in 2 randomized, double-blind, placebo-controlled, Phase 1 studies. In the first-in-human study, single-ascending oral doses of nafithromycin (100 to 1200 mg) were administered to subjects under fasted or fed condition, with effects of food on bioavailability of nafithromycin studied at the dose levels of 400 and 800 mg. In the second study, multiple-ascending oral doses of 600, 800, or 1000 mg of nafithromycin were administered once daily for 7 days under a fed condition. Nafithromycin was generally well tolerated at all doses. No serious or severe adverse events were observed. The mean maximum plasma concentration (Cmax) ranged from 0.099 to 1.742 mg/L, and the area under the concentration-time curve from time zero to time t (AUC0-t ) ranged from 0.54 to 22.53 h⋅mg/L. Nafithromycin plasma AUC0-t increased approximately 1.2-fold under fed compared to fasted condition. In the multiple-dose study, the Day 7 nafithromycin Cmax ranged from 1.340 to 2.987 mg/L and the AUC over the final dosing interval (AUC0-24) ranged from 13.48 to 43.46 h⋅mg/L. The steady state was achieved after 3 days for the 600 mg and 800 mg dose cohorts and after 4 days for the 1000 mg cohort. Under both single- and multiple-dosing regimens, plasma exposure to nafithromycin appeared to increase more than dose-proportionally. Nafithromycin showed moderate accumulation on Day 7 of dosing. The human pharmacokinetic profile, safety and tolerability data support further development of nafithromycin.

Safety, Pharmacokinetics, and Food Effect of Tebipenem Pivoxil Hydrobromide after Single and Multiple Ascending Oral Doses in Healthy Adult Subjects

Tebipenem pivoxil hydrobromide (TBPM-PI-HBr, formerly SPR994) is an orally available prodrug of tebipenem, a carbapenem with activity versus multidrug-resistant (MDR) Gram-negative pathogens, including quinolone-resistant and extended-spectrum-β-lactamase-producing Enterobacteriaceae The safety and pharmacokinetics (PK) of tebipenem were studied after administration of single and multiple ascending oral doses of TBPM-PI-HBr in fed and fasted states. Healthy adults received single oral doses of TBPM-PI-HBr at 100 mg to 900 mg or placebo (n = 108) or multiple doses of 300 mg or 600 mg every 8 h or placebo (n = 16) for 14 days. In the single-ascending-dose (SAD) phase, mean tebipenem plasma concentrations increased in a linear and dose proportional manner for doses of 100 to 900 mg and were comparable in the fasted and fed states for the 300- and 600-mg doses. In the MAD phase, tebipenem maximum concentration (C max) was reached within 1.5 h and was dose proportional on day 1 and higher than dose proportional (2.7-fold) on day 14. AUC was more than 2-fold greater on day 1 (2.7-fold) and day 14 (2.5-fold) for 600 mg q8h than for 300 mg q8h. Approximately 55% to 60% of tebipenem was recovered in the urine. TBPM-PI-HBr was well tolerated; mild, transient diarrhea was the most commonly reported adverse event. TBPM-PI-HBr provides an orally bioavailable carbapenem option to treat serious infections caused by MDR Enterobacteriaceae and has the potential to decrease the need for intravenous antibiotic therapy in the hospital or outpatient setting. (This study has been registered at ClinicalTrials.gov under identifier NCT03395249.).

Multiple Ascending Oral Dose 14-Day Trial of LHF-535 in Healthy Participants

Multiple Ascending Oral Dose 14-Day Trial of LHF-535 in Healthy Participants

Multiple-dose clinical pharmacology of ACT-541468, a novel dual orexin receptor antagonist, following repeated-dose morning and evening administration

ACT-541468 is a dual orexin receptor antagonist with sleep-promoting effects in humans. Following entry-into-humans, its pharmacokinetics (PK) including dose-proportionality and accumulation, pharmacodynamics (PD), safety, and tolerability following multiple-ascending oral dose (MAD) administration in the morning, and next-day residual effects after repeated evening administration were investigated in a double-blind, placebo-controlled, randomized study. 31 healthy male and female subjects in 3 dose-groups (10, 25, and 75 mg) received study drug in the morning for 5 days (MAD part), and 20 healthy subjects received 25 mg in the evening for 1 week (evening part). PK, PD (saccadic peak velocity (SPV), adaptive tracking, body sway, Bond and Lader visual analogue scales (VAS), Karolinska Sleepiness Scale (KSS), VAS Bowdle for assessment of psychedelic effects), Digit Symbol Substitution Test (DSST), and Simple Reaction Time Test (SRTT), safety, and tolerability were assessed. ACT-541468 was absorbed with a median tmax of 1.0–2.0 h across the 3 dose groups. The geometric mean elimination half-life (t½) on Day 5 was between 5.6 and 8.5 h, and the exposure (area under the curve (AUC)) showed dose proportionality. No accumulation and no influence of sex on the multiple-dose PK parameters of ACT-541468 was observed. No effects were observed at 10 mg. Administration of 25 and 75 mg during the day showed clear dose-dependent effects on the PD parameters, while next-day effects were absent after evening administration of 25 mg. The drug was safe and well tolerated. In conclusion, multiple-dose PK/PD of ACT-541468 were compatible with a drug designated to treat insomnia.

Evaluate The Safety, Tolerability and Pharmacokinetics Of Multiple Ascending Oral Doses Of WCK 4873 In Healthy Adult Volunteers

Evaluate The Safety, Tolerability and Pharmacokinetics Of Multiple Ascending Oral Doses Of WCK 4873 In Healthy Adult Volunteers

Abstract TMP91: Phase I Assessment of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the Oral Protease-activated Receptor-4 Antagonist BMS-986120

Introduction: BMS-986120 is a potent and selective oral antagonist of protease-activated receptor-4 (PAR4), a thrombin-activated platelet receptor thought to be important in thrombus propagation and pathological vascular occlusion. PAR4 antagonism has potential therapeutic utility in the treatment and prevention of thrombotic diseases. Preclinical arterial thrombosis models showed greater efficacy than current antithrombotics, including aspirin, clopidogrel and vorapaxar, with lower bleeding risk. Hypothesis: This report presents results from the initial Phase I randomized, double-blind, placebo-controlled single- and multiple-ascending oral dose studies of BMS-986120. Methods: To assess the pharmacokinetics (PK), pharmacodynamics (PD), safety profile and tolerability of BMS-986120, single doses of BMS-986120 from 0.5-180 mg were administered to 42 healthy subjects and multiple doses of 2.5-100 mg daily for up to 14 days to 24 subjects, randomized with placebo. Results: BMS-986120 PK showed rapid absorption and distribution with slow terminal elimination. Exposures increased in a dose related manner. BMS-986120 selectively inhibited PAR4 agonist peptide (PAR4-AP) induced ex-vivo platelet aggregation and p-selectin expression in a dose- and concentration-dependent manner. Complete inhibition of induced platelet aggregation for at least 24 hours was observed in all subjects with doses ≥10 mg daily. PAR1 platelet activation was unaffected. Treatment-emergent adverse events (AEs) were reported at a frequency similar to placebo. There were no drug-related discontinuations or bleeding-related clinical findings or AEs. Laboratory assessments, including routine coagulation tests and template bleeding times, showed no clinically relevant trends. Conclusions: BMS-986120 was safe and well tolerated by healthy subjects. These results represent the first reported clinical experience of a selective oral PAR4 antagonist.

A phase 1 study to evaluate the safety and pharmacokinetics of PQ912, a glutaminyl cyclase inhibitor, in healthy subjects

IntroductionPyroglutamate-amyloid-β (pE-Aβ) peptides are major components of Aβ-oligomers and Aβ-plaques, which are regarded as key culprits of Alzheimer's disease (AD) pathology. PQ912 is a competitive inhibitor of the enzyme glutaminyl cyclase (QC), essential for the formation of pE-Aβ peptides. MethodsA randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study investigated the safety, pharmacokinetics, and pharmacodynamics of PQ912 in healthy nonelderly and elderly subjects. ResultsPQ912 was considered safe and well tolerated with dose-proportional pharmacokinetics up to doses of 200 mg. At higher doses up to 1800 mg, exposure was supraproportional and exposure in elderly subjects was approximately 1.5- to 2.1-fold higher. Exposure in cerebrospinal fluid (CSF) was approximately 20% of the unbound drug in plasma, and both serum and CSF QC activity was inhibited in a dose-related manner. DiscussionThis first-in-man study of a compound-targeting QC inhibition justifies further development of PQ912 for the treatment of AD.

A first-in-human randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study of novel spiroindolone KAE609, to assess the safety, tolerability and pharmacokinetics in healthy adult volunteers

A first-in-human randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study of novel spiroindolone KAE609, to assess the safety, tolerability and pharmacokinetics in healthy adult volunteers

A first-in-human randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study of novel Imidazolopiperazine KAF156 to assess its safety, tolerability, and pharmacokinetics in healthy adult volunteers.

KAF156 belongs to a new class of antimalarial, the imidazolopiperazines, and is currently in clinical development for the treatment of uncomplicated malaria. This first-in-human, single- and multiple-ascending-dose study in 70 healthy male volunteers determined the maximum oral dose of KAF156 tolerated by healthy adults and derived pharmacokinetic data (including preliminary food effect) to enable dose calculations for malaria patients. KAF156 was studied in single-dose cohorts (10 to 1,200 mg, including one 400-mg food effect cohort (4 to 10 subjects/cohort), and in multiple-dose cohorts (60 to 600 mg once daily for 3 days; 8 subjects/cohort). The follow-up period was 6 to 14 days after the last dose. KAF156 was tolerated, with self-limited mild to moderate gastrointestinal and neurological adverse events. In treated subjects after single doses, headache (n = 4; 11.1%), diarrhea (n = 3; 8.3%), dizziness (n = 3; 8.3%), and abdominal pain (n = 2; 5.6%) were the most common adverse events. Headache (n = 4; 16.7%), nausea (n = 3; 12.5%), upper respiratory tract infection (n = 3; 12.5%), and dizziness (n = 2; 8.3%) were the most common adverse events following multiple doses. KAF156 time to maximum concentration (Tmax) was between 1.0 and 6.0 h. Both the area under the concentration-time curve (AUC) and maximum concentration (Cmax) increased more than dose-proportionally in both single- and multiple-ascending-dose cohorts (terminal half-life, 42.5 to 70.7 h). There was no significant accumulation over 3-day repeated administration. The extent of absorption was not significantly affected by food at a single dose of 400 mg, while mean Cmax decreased from 778 ng/ml to 627 ng/ml and Tmax was delayed from a median of 3.0 h under fasting conditions to 6.0 h under fed conditions. Renal elimination is a minor route.

A first-in-human randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study of novel antimalarial Spiroindolone KAE609 (Cipargamin) to assess its safety, tolerability, and pharmacokinetics in healthy adult volunteers.

This first-in-human randomized, double-blind, placebo-controlled, ascending-single and -multiple oral dose study was designed to evaluate the safety, tolerability, and pharmacokinetics in healthy volunteers of KAE609 (cipargamin; formerly NITD609), a spiroindolone now in trials for malaria treatment. It was studied in single-dose cohorts (1 to 300 mg, including one 30-mg food effect cohort) with 4 to 10 subjects in each cohort and in multiple-dose cohorts (10 to 150 mg once daily for 3 days) with 8 subjects in each cohort. The follow-up period was 6 to 8 days post-last dose. Safety and pharmacokinetics were assessed at scheduled time points during the study. Systemic exposure in terms of the area under the concentration-time curve from 0 h extrapolated to infinity (AUC0–∞) increased in a dose-proportional manner over the dose range of 1 to 300 mg. The AUC from time zero to the time of the last quantifiable concentration (AUClast) and the maximum concentration of drug in plasma (Cmax) also increased in an approximately dose-proportional manner. When administered daily for 3 days, the accumulation ratio on day 3 (the AUC from time zero to 24 h postdosing [AUC0–24] on day 3/AUC0–24 on day 1) was in the range of 1.5 to 2 in the studied dose range (10 to 150 mg) and was consistent with an elimination half-life of around 24 h. Urine analysis for unchanged KAE609 revealed negligible amounts (≤0.01%) were excreted renally. The high fat food intake did not affect the extent of KAE609 absorption (AUC); however, the Cmax was reduced by around 27%. KAE609 was tolerated in this study, with transient gastrointestinal and genitourinary adverse events of mild to moderate intensity (semen discoloration, diarrhea, nausea and abdominal discomfort, dizziness and headache, catheter site hematoma). Gastrointestinal and genitourinary adverse events increased with rising doses.

A First-in-Human, Randomized, Double-Blind, Placebo-Controlled, Single- and Multiple-Ascending Oral Dose Study To Assess the Safety and Tolerability of LFF571 in Healthy Volunteers

Clostridium difficile is the leading cause of hospital-acquired infectious diarrhea. LFF571 is a novel inhibitor of the prokaryotic translation elongation factor Tu and is active against a range of bacterial species, including C. difficile. This first-in-human study investigated the safety and pharmacokinetics of single and multiple ascending oral doses of LFF571 in healthy subjects. This was a randomized, double-blind, placebo-controlled study. Except for one cohort, LFF571 was given with a high-fat meal to all single-dose cohorts (25 mg, 100 mg, 400 mg, and 1,000 mg). In the multiple-dose cohorts (25 mg, 100 mg, or 200 mg every 6 h for 10 days), LFF571 was given without regard to food. A total of 56 subjects completed the study, with 32 and 25 receiving single and multiple doses, respectively. There were no deaths, no serious adverse events, and no subject withdrawals due to an adverse event. The most common adverse event was diarrhea; gastrointestinal pain or distension was also noted. Diarrhea did not develop more frequently among subjects who received LFF571 than among those who received a placebo. LFF571 had limited systemic exposure and high steady-state fecal concentrations. The highest concentration of LFF571 in serum (3.2 ng/ml) was observed after the last dose in a subject who received 200 mg every 6 h for 10 days. LFF571 was generally safe and well tolerated in single and multiple oral doses in healthy subjects. The minimal serum and high fecal concentrations support the further development of LFF571 for the treatment of C. difficile infections.