A phase 1 evaluation of the pharmacokinetic/pharmacodynamic interaction of the anti-malarial agents KAF156 and piperaquine

KAF156 is a novel imidazolopiperazine anti-malarial with activity against pre-erythrocytic liver stages, asexual and sexual blood stages. Based on in vitro data, a two-way pharmacokinetic interaction was hypothesized for KAF156 use in combination with piperaquine (PPQ) as both drugs are CYP3A4 substrates and inhibitors. Potential combination effects on the QT interval were also assessed.

This was an open-label, parallel-group, single-dose study in healthy volunteers randomized to three parallel arms (1:1:1) of 800 mg KAF156 + 1280 mg PPQ, 800 mg KAF156 alone and 1280 mg PPQ alone. Triplicate ECGs were done up to 48 h post-dose. Routine safety and pharmacokinetic assessments were carried out up to 61 days.

Of the 72 healthy male subjects recruited, 68 completed the study. Co-administration of PPQ and KAF156 had no overall effect on AUC of either compound, but the Cmax values of both KAF156 (~ 23%) and piperaquine (~ 70%) increased. Both drugs given alone or in combination were well tolerated with no deaths or serious adverse events (SAEs). AEs were observed at the frequency of 87.5, 79.2 and 58.3% respectively for KAF156 + PPQ, PPQ and KAF156 arms. The most common AEs were nausea and headache. There were no Grade 3 or 4 events. There were no ECG related AEs, no QTcF interval > 480 ms and no QTcF interval increase from baseline > 60 ms. There was a positive ∆QTcF trend in the KAF156 + PPQ arm when either KAF156 or piperaquine concentration increases, but there was no significant difference between the combination arm and other arms in maximum ∆QTcF.

No safety/cardiac risk or drug interaction was identified which would preclude use of a KAF156 and PPQ combination in future studies.