First-Time-in-Human Study and Prediction of Early Bactericidal Activity for GSK3036656, a Potent Leucyl-tRNA Synthetase Inhibitor for Tuberculosis Treatment.

This first-time-in-human (FTIH) study evaluated the safety, tolerability, pharmacokinetics, and food effect of single and repeat oral doses of GSK3036656, a leucyl-tRNA synthetase inhibitor. In part A, GSK3036656 single doses of 5 mg (fed and fasted), 15 mg, and 25 mg and placebo were administered. In part B, repeat doses of 5 and 15 mg and placebo were administered for 14 days once daily. GSK3036656 showed dose-proportional increase following single-dose administration and after dosing for 14 days. The maximum concentration of drug in serum (Cmax) and area under the concentration-time curve from 0 h to the end of the dosing period (AUC0-τ) showed accumulation with repeated administration of approximately 2- to 3-fold. Pharmacokinetic parameters were not altered in the presence of food. Unchanged GSK3036656 was the only drug-related component detected in plasma and accounted for approximately 90% of drug-related material in urine. Based on total drug-related material detected in urine, the minimum absorbed doses after single (25 mg) and repeat (15 mg) dosing were 50 and 78%, respectively. Unchanged GSK3036656 represented at least 44% and 71% of the 25- and 15-mg doses, respectively. Clinical trial simulations were performed to guide dose escalation during the FTIH study and to predict the GSK3036656 dose range that produces the highest possible early bactericidal activity (EBA0-14) in the prospective phase II trial, with consideration of the predefined exposure limit. GSK3036656 was well tolerated after single and multiple doses, with no reports of serious adverse events. (This study has been registered at ClinicalTrials.gov under identifier NCT03075410.).

Pharmacokinetics and absolute bioavailability of mepolizumab following administration at subcutaneous and intramuscular sites.

This study characterized the pharmacokinetics (PK) of mepolizumab, after a single intravenous (IV), subcutaneous (SC), or intramuscular (IM) dose in healthy adults and determined the absolute bioavailability of SC and IM mepolizumab delivered at different anatomical regions. Sixty healthy subjects were randomly assigned to receive a single dose of either mepolizumab 250 mg by IV, SC injection (upper arm, abdomen, or thigh); or IM injection (thigh). Following IV administration, the mean maximum observed plasma mepolizumab concentration (Cmax ) and the mean area under the concentration versus time curves from time zero to infinity (AUC(0-∞) ) were 109 ± 17 µg/mL and 1,557 ± 250 µg d/mL, respectively. After SC administration, the mean (±SD) values of Cmax and AUC(0-∞) were 34.1-38.2 ± 7.3-12.1 µg/mL and 1,110-1,238 ± 228-372 µg d/mL, respectively. Following IM administration, the mean values of Cmax and AUC(0-∞) were 46.9 ± 10.6 µg/mL and 1,395 ± 348 µg d/mL. The median terminal half-life was similar for SC, IM and IV administration (17.9-20.4, 19.2, and 18.5 days, respectively). The overall mean bioavailability of SC mepolizumab was 64-75%, and absorption was relatively similar for the three SC injection sites. Mepolizumab 250 mg was generally well tolerated in this study. These results support flexibility in the SC injection site for mepolizumab.

Radical curative efficacy of tafenoquine combination regimens in Plasmodium cynomolgi-infected Rhesus monkeys (Macaca mulatta).

BACKGROUND: Tafenoquine is an 8-aminoquinoline being developed for radical cure (blood and liver stage elimination) of Plasmodium vivax. During monotherapy treatment, the compound exhibits slow parasite and fever clearance times, and toxicity in glucose-6-phosphate dehydrogenase (G6PD) deficiency is a concern. Combination with other antimalarials may mitigate these concerns. METHODS: In 2005, the radical curative efficacy of tafenoquine combinations was investigated in Plasmodium cynomolgi-infected naïve Indian-origin Rhesus monkeys. In the first cohort, groups of two monkeys were treated with a three-day regimen of tafenoquine at different doses alone and in combination with a three-day chloroquine regimen to determine the minimum curative dose (MCD). In the second cohort, the radical curative efficacy of a single-day regimen of tafenoquine-mefloquine was compared to that of two three-day regimens comprising tafenoquine at its MCD with chloroquine or artemether-lumefantrine in groups of six monkeys. In a final cohort, the efficacy of the MCD of tafenoquine against hypnozoites alone and in combination with chloroquine was investigated in groups of six monkeys after quinine pre-treatment to eliminate asexual parasites. Plasma tafenoquine, chloroquine and desethylchloroquine concentrations were determined by LC-MS in order to compare doses of the drugs to those used clinically in humans. RESULTS: The total MCD of tafenoquine required in combination regimens for radical cure was ten-fold lower (1.8 mg/kg versus 18 mg/kg) than for monotherapy. This regimen (1.8 mg/kg) was equally efficacious as monotherapy or in combination with chloroquine after quinine pre-treatment to eliminate asexual stages. The same dose of (1.8 mg/kg) was radically curative in combination with artemether-lumefantrine. Tafenoquine was also radically curative when combined with mefloquine. The MCD of tafenoquine monotherapy for radical cure (18 mg/kg) appears to be biologically equivalent to a 600-1200 mg dose in humans. At its MCD in combination with blood schizonticidal drugs (1.8 mg/kg), the maximum observed plasma concentrations were substantially lower than (20-84 versus 550-1,100 ng/ml) after administration of 1, 200 mg in clinical studies. CONCLUSIONS: Ten-fold lower clinical doses of tafenoquine than used in prior studies may be effective against P. vivax hypnozoites if the drug is deployed in combination with effective blood-schizonticidal drugs.