Randomized, placebo‐controlled, double‐blind phase I trial of co‐administered pyronaridine and piperaquine in healthy adults of sub‐Saharan origin

Abstract Drug resistance to sulfadoxine‐pyrimethamine and amodiaquine threatens the efficacy of malaria chemoprevention interventions in children and pregnant women. Combining pyronaridine (PYR) and piperaquine (PQP), both components of approved antimalarial therapies, has the potential to protect vulnerable populations from severe malaria. This randomized, double‐blind, placebo‐controlled (double‐dummy), parallel‐group, single site phase I study in healthy adult males or females of Black sub‐Saharan African ancestry investigated the safety, tolerability, and pharmacokinetics of PYR + PQP (n = 15), PYR + placebo (n = 8), PQP + placebo (n = 8), and double placebo (n = 6) administered orally once daily for 3 days at the registered dose for the treatment of uncomplicated malaria. All participants completed the study. Forty‐five adverse events were reported in 26 participants, most (41/45) were mild/moderate in severity, with no serious adverse events, deaths, or study withdrawals. Adverse events were reported in 66.7% (10/15) of participants administered PYR + PQP, 87.5% (7/8) with PYR + placebo, 50.0% (4/8) with PQP + placebo, and 83.3% (5/6) with placebo. For PYR containing regimens, five of 23 participants had asymptomatic transient increases in alanine and/or aspartate aminotransferase. With PQP containing regimens, four of 23 participants had mild Fridericia‐corrected QT interval prolongation. Liver enzyme elevations and prolonged QTc interval were consistent with observations for PYR‐artesunate and dihydroartemisinin‐PQP, respectively, administered to healthy adults and malaria patients. Increases in PYR and PQP exposures were observed following co‐administration versus placebo, with substantial interparticipant variability. The findings suggest that PYR + PQP may have potential in chemoprevention strategies. Further studies are needed in the target populations to assess chemoprotective efficacy and define the benefit–risk profile, with special considerations regarding hepatic and cardiac safety.


CONTENTS
Participant identifiers (A to E) are indicated adjacent to the relevant data point.
Severely deranged ALT (>5xULN) and moderately deranged AST (>4xULN) and GGT (>3xULN).The transaminases were first elevated on D3, (ALT 63 IU/L, AST 59 IU/L).By D4 they fulfilled the AESI criteria with moderately elevated ALT (>3xULN) and AST (>4xULN).Levels peaked on D5, severely elevated ALT (>5xULN) and moderately elevated AST (>4xULN).From D6 onwards the LFTs began to recover.By D8, the ALT was down to 2xULN and the AST was only mildly raised at 52 IU/L.By D15 both transaminase levels were back to normal.There were no clinically significant bilirubin rises throughout the period of elevated LFTs up to Day 30.The participant remained asymptomatic throughout and no concomitant medications were required.They did not experience any relevant symptoms such as fatigue, nausea, vomiting, right upper quadrant pain, fever or rash.There were no clinically significant changes in vital signs, physical examination, ECG/telemetry or urinalysis.Of note, the participant was positive for anti-HBc IgG/IgM but negative for anti-HBc IgM at screening.Given that remaining hepatitis serology was negative, this is likely in keeping with past, resolved infection.
Given the known safety profile of PYR in previous Phase 1 studies, and the temporal correlation to dosing, this was deemed to be related to drug administration and graded severe as per protocol.
The ALT was first raised on D3 at 148 IU/L, nearly 3xULN.ALT and AST peaked on D4 fulfilling AESI criteria as the ALT was 171 IU/L (>3xULN).The AST was >2xULN at 96 IU/L.On the same day, the participant's bilirubin was normal at 4 µmol/L (ULN 20 µmol/L), ALP at 107 IU/L (ULN 129 IU/L) and GGT was high at 114 IU/L (ULN 71).From D5 onwards the LFTs began to recover.By D8 the ALT was only mildly raised (71 IU/L), AST was within normal limits and GGT close to normal 78 (ULN 71 IU/L).All LFTs were within normal range on D15.Total bilirubin and ALP remained within normal range throughout the study.The participant remained asymptomatic throughout and no concomitant medications were required.They did not experience any relevant symptoms such as fatigue, nausea, vomiting, RUQ pain, fever, rash or an associated eosinophilia.There were no clinically significant changes in vital signs, physical examination, ECG/telemetry or urinalysis.Of note, Participant 10007 was positive for anti-HBc IgG/IgM but negative for anti-HBc IgM at screening.Given that remaining hepatitis serology was negative, this is likely in keeping with past, resolved infection.Given the known safety profile of PYR in previous Phase 1 studies, and the temporal correlation to dosing, this was deemed to be drug related and graded moderate as per protocol.

Figure
Figure S1 Frequency of treatment-emergent adverse events of any cause following administration of

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Figure S2 Drug exposure to pyronaridine based on (a) AUC0-t and (b) Cmax for participants with or

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Figure S3Relationship between maximum values of (a) alanine aminotransferase (ALT) or (b)

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Figure S1 Frequency of treatment-emergent adverse events of any cause following administration

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Figure S2 Drug exposure to pyronaridine based on (a) AUC0-t and (b) Cmax for participants with or

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Figure S4 Changes in blood pressure.
; PQP, piperaquine; QTcF, Fridericia-corrected QT.Values are number of participants.There were no absolute QTcF values >480 msec or changes in QTcF from baseline >60 msec at any time point.

Table S1 Participant baseline demographics.
a Denominator is number of women.
The temporal pattern of LFT elevations in this study participant was different from the other volunteers who also showed an ALT/AST elevation signal.AST first elevated D15, peaking on D25 at >3xULN (116 IU/L).ALT was first elevated on D15, again peaked D25 at >5xULN (182 IU/L).Thus, fulfilling AESI criteria.A recent Epstein Barr Virus (EBV) infection was documented on subsequent liver safety screening tests.Hepatitis C, Hepatitis B, Hepatitis A, and Hepatitis E serologies were negative.LFTS were returning to normal on unscheduled bloods taken on D49, ALT 65 IU/L (ULN 35 IU/L) and AST 45 IU/L (ULN 31 IU/L).Bilirubin, ALP and GGT remained within normal range throughout the study.The elevation of transaminases was associated with a lymphocytosis starting on Day 22. Lymphocytes 3.86 x 10 9 /L (ULN 3.65) returning to normal on Day 28.Given the temporal relationship to dosing and documented acute EBV infection, this was deemed not drug related and graded as severe per protocol.Asymptomatic elevation of transaminases starting at D3 (AST and ALT >5xULN).Peak values D3 were ALT 766 IU/L (21.9xULN) and AST 649 IU/L (20.9xULN).ALP was high at 119 IU/L (ULN 104) as was GGT at 110 IU/L (ULN 42).On the same day, abdominal ultrasound scan was performed and showed normal appearance of liver.An area of calcification in the right lobe was suggestive of hepatic granuloma.Additionally, no solid focal lesion was seen.Hepatitis C, Hepatitis B, Hepatitis A, and Hepatitis E serologies were negative.ALT and AST values slowly returned to normal by D22 without treatment or medication, as well as ALP and GGT.Bilirubin remained within normal range throughout the study.Given the known safety profile of PYR in previous Phase 1 studies and temporal relationship to dosing, this was deemed drug related.