Combining SJ733, an oral ATP4 inhibitor of Plasmodium falciparum, with the pharmacokinetic enhancer cobicistat: An innovative approach in antimalarial drug development

Abstract

Background: SJ733, a newly developed inhibitor of P. falciparum ATP4, has a favorable safety profile and rapid antiparasitic effect but insufficient duration to deliver a single-dose cure of malaria. We investigated the safety, tolerability, and pharmacokinetics of a multidose SJ733 regimen and a single-dose pharmacoboost approach using cobicistat to inhibit CYP3A4, thereby increasing exposure.

Methods: Two multidose unboosted cohorts (n = 9) (SJ733, 300 mg and 600 mg daily for 3 days) followed by three single-dose boosted cohorts combining SJ733 (n = 18) (75-, 300-, or 600-mg single dose) with cobicistat (150-mg single dose) as a pharmacokinetic booster were evaluated in healthy volunteers (ClinicalTrials.gov: NCT02661373).

Findings: All participants tolerated SJ733 well, with no serious adverse events (AEs), dose-limiting toxicity, or clinically significant electrocardiogram or laboratory test findings. All reported AEs were Grade 1, clinically insignificant, and considered unlikely or unrelated to SJ733. Compared to unboosted cohorts, the SJ733/cobicistat-boosted cohorts showed a median increase in area under the curve and maximum concentration of 3·9 × and 2·6 ×, respectively, and a median decrease in the ratio of the major CYP3A-produced metabolite SJ506 to parent drug of 4·6 × . Incorporating these data in a model of parasite dynamics indicated that a 3-day regimen of SJ733/cobicistat (600 mg/150 mg daily) relative to a single 600-mg dose ± cobicistat would increase parasite clearance from 106 to 1012 parasites/µL.

Interpretation: The multidose and pharmacoboosted approaches to delivering SJ733 were well-tolerated and significantly increased drug exposure and prediction of cure. This study supports the further development of SJ733 and demonstrates an innovative pharmacoboost approach for an antimalarial.

Funding: Global Health Innovative Technology Fund, Medicines for Malaria Venture, National Institutes of Health, and American Lebanese Syrian Associated Charities.

Keywords: Antimalarial; Pharmacoboost; Pharmacodynamics; Pharmacokinetics; SJ733.

Conflict of interest statement

A.H.G. and BBF III received grant funding from the GHIT and MMV. J.C.P. received grant funding from the GHIT and the NIH Cancer Center Support Grant P30 CA021765. R.D., T.B.S., L.T., E.J., K.C.B., S.O., N.D.P., R.N.H., J.T.H., F.G., N.M., and T.Y. received grant funding from the GHIT. P.M.F. is a member of the Merck Safety Monitoring Committee. J.S.M. received funding from the Australian National Health and Medical Research Council (NHMRC) Practitioner Fellowship (GNT1135955) and NHMRC grant Programme (GNT1132975). R.K.G. receives grant funding from and is a reviewer for the GHIT and MMV. He is also an inventor on a patent disclosing SJ733, which may generate revenue if licensed. A.M.S., J.L.R, L.B., and S.C. have no conflicts to declare.

Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.

Figures

Figure 1

Consort Flow Diagram of the Phase 1a study: Multidose and cobicistat boosted dose cohorts. Flow diagram of participant progress through the study. In Phase 1a, multiple ascending doses and cobicistat-boosted doses of SJ733 were tested in two (300 mg and 600 mg SJ733 daily for 3 days, respectively) and three (75, 300, and 600 mg SJ733 combined with 150 mg cobicistat, single-dose) fasting dose cohorts, respectively. Enrolment in more than one non-consecutive dose cohort was allowed with at least 14 days required between doses.

Figure 2

SJ733 median concentration versus time plot for unboosted and cobicistat-boosted single-dose cohorts. Estimated minimum inhibitory concentration (150 ng/mL) is shown as a horizontal red line. Abbreviations: Cobi, cobicistat; × 3 QD, daily for 3 days.

Figure 3

Secondary PK parameters after single-dose or multidose treatment with SJ733 alone or single-dose SJ733 phamacoboosted with cobicistat. (a) Apparent clearance (CL/F), (b) areas under the curve (AUC), (c) maximum concentration (Cmax), and (d) time above 150 ng/mL, the minimum inhibitory concentration (MIC), are stratified by cohort. Horizontal Bar: median; Box: quartile range; Whiskers: range. Red dots: individual measures.

Figure 4

PK/PD simulations of the efficacy of SJ733 alone and SJ733 pharmacoboosted with cobicistat to cure malaria. (a) PK/PD model simulation of the effect of single-dose SJ733 (600 mg) alone (light gray) and that predicted for the same dose of SJ733 pharmacoboosted with cobicistat (dark gray). (b-c) The same simulations were used to assess multidose SJ733 (b: 300 mg daily for 3 days ± cobicistat and c: 600 mg daily for 3 days ± cobicistat).