Search

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

Background Artemether-lumefantrine (AL) dispersible formulation was developed for the treatment of uncomplicated Plasmodium falciparum malaria in infants and children weighing 5 to 28 days and

For an effective antimalarial therapy, maintenance of antimalarial drug concentrations well above minimum parasiticidal concentration for certain time duration is required in the target compartments (eg., blood, liver). On the other hand, malaria parasite infection may affect few physiological functions (eg., hepatic metabolism, protein binding) that may affect the pharmacokinetics and tissue disposition of antimalarial drugs. The altered PK in turn can affect the concentrations of the drugs and consequently their efficacy. Therefore, this work was undertaken to understand whether there is any difference in the pharmacokinetics (PK) of currently approved/available antimalarial drugs between malaria patients and healthy subjects. The pharmacokinetic data of approved drugs was obtained from various public resources and the data was compiled for absorption, distribution, metabolism and elimination (ADME) properties. These ADME properties were further analyzed against the information available on reported physiological changes (e.g. reduced hepatic blood flow in patients, changes in CYP enzyme levels, etc.) to understand the possible contributing factors for potential alterations in the pharmacokinetics of drugs in patients. Pre-clinical information available for these drugs were also retrieved and used for the present investigation. The results indicated that there was a significant alteration in the pharmacokinetic properties of most of the currently available/ approved antimalarial drugs in malarial patients compared to healthy subjects. The correlation analysis indicated that physiological changes such as hepatic blood flow, CYP enzyme expression/activity and protein binding may be the potential reasons for the observed differences. This analysis could be useful to envisage changes in the PK properties of the drugs based on their ADME properties and further aid in the development of future antimalarial drugs.

Background Artemether-lumefantrine (Coartem®; AL) is a standard of care for malaria treatment as an oral six-dose regimen, given twice daily over three days with one to four tablets (20/120 mg) per dose, depending on patient body weight. In order to reduce the pill burden at each dose and potentially enhance compliance, two novel fixed-dose tablet formulations (80/480 mg and 60/360 mg) have been developed and tested in this study for bioequivalence with their respective number of standard tablets. Methods A randomized, open-label, two-period, single-dose, within formulation crossover bioequivalence study comparing artemether and lumefantrine exposure between the novel 80/480 mg tablet and four standard tablets, and the novel 60/360 mg tablet and three standard tablets, was conducted in 120 healthy subjects under fed conditions. Artemether, dihydroartemisinin, and lumefantrine were measured in plasma by HPLC/UPLC-MS/MS. Pharmacokinetic (PK) parameters were determined by non-compartmental analyses. Results Adjusted geometric mean AUClast for artemether were 345 and 364 ng·h/mL (geometric mean ratio (GMR) 0.95; 90% CI 0.89-1.01) and for lumefantrine were 219 and 218 μg·h/mL (GMR 1.00; 90% CI 0.93-1.08) for 80/480 mg tablet versus four standard tablets, respectively. Corresponding Cmax for artemether were 96.8 and 99.7 ng/mL (GMR 0.97; 90% CI 0.89-1.06) and for lumefantrine were 8.42 and 8.71 μg/mL (GMR 0.97; 90% CI 0.89-1.05). For the 60/360 mg tablet versus three standard tablets, adjusted geometric mean AUClast for artemether were 235 and 231 ng·h/mL (GMR 1.02; 90% CI 0.94-1.10), and for lumefantrine were 160 and 180 μg·h/mL (GMR 0.89; 90% CI 0.83-0.96), respectively. Corresponding Cmax for artemether were 75.5 and 71.5 ng/mL (GMR 1.06; 90% CI 0.95-1.18), and for lumefantrine were 6.64 and 7.61 μg/mL (GMR 0.87; 90% CI 0.81-0.94), respectively. GMR for Cmax and AUClast for artemether and lumefantrine for all primary comparisons were within the bioequivalence acceptance criteria (0.80-1.25). In addition, secondary PK parameters also met bioequivalence criterion. Conclusion Both of the novel artemether-lumefantrine tablet formulations evaluated are bioequivalent to their respective standard Coartem® tablet doses. These novel formulations are easy to administer and may improve adherence in the treatment of uncomplicated malaria caused by Plasmodium falciparum. Trial registration Clinical trial registration number: CTRI/2011/12/002256