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

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.

Performance testing protocol for closed-system transfer devices used during pharmacy compounding and administration of hazardous drugs.

OBJECTIVES: The United States National Institute for Occupational Safety and Health (NIOSH) is developing a protocol to assess the containment performance of closed system transfer devices (CSTDs) when used for drug preparation (task 1) and administration (task 2) and published a draft protocol in September 2016. Nine possible surrogates were proposed by NIOSH for use in the testing. The objectives of this study were to: (A) select the most appropriate surrogate; (B) validate the NIOSH protocol using this surrogate; and (C) determine the containment performance of four commercial CSTDs as compared with an open system of needle and syringe using the validated NIOSH protocol. METHODS: 2-Phenoxyethanol (2-POE) was selected as a surrogate based on its water solubility, Henry's volatility constant, detectability by mass spectrometry, and non-toxicity. Standard analytical validation methods including system suitability, limit of detection (LOD), and limit of quantitation (LOQ) as well as system cleaning validation were performed. The amount of 2-POE released when the CSTDs were manipulated according to two tasks defined by NIOSH was determined using mass spectrometry coupled to thermal desorption and gas chromatography. This approach allows sensitivity of detection below 1 part per billion (ppb). Equashield, Tevadaptor (OnGuard), PhaSeal, and ChemoClave were assessed according to manufacturers' instructions for use. RESULTS: 2-POE was tested and validated for suitability of use within the NIOSH protocol. A simple and efficient cleaning protocol achieved consistently low background values, with an average value, based on 85 measurements, of 0.12 ppb with a 95% confidence interval (CI) of ±0.16 ppb. This gives an LOD for the tests of 0.35 ppb and an LOQ of 0.88 ppb. The Equashield, Tevadaptor (OnGuard), and PhaSeal devices all showed average releases, based on 10 measurements from five tests, that were less than the LOQ (i.e. < 0.88 ppb), while the ChemoClave Vial Shield with Spinning Spiros showed average releases of 2.9±2.3 ppb and 7.5±17.9 ppb for NIOSH tasks 1 and 2 respectively at the 95% confidence level. The open system of needle and syringe showed releases, based on two measurements from a single test, of 4.2±2.2 ppb and 5.1±1.7 ppb for NIOSH tasks 1 and 2 respectively at the 95% confidence level. CONCLUSIONS: 2-POE proved to be an ideal surrogate for testing of CSTDs using the NIOSH protocol. We propose that a CSTD can be qualified using the NIOSH testing approach if the experimental LOQ is less than 1 ppb and the release values are below the LOQ. Equashield, Tevadaptor (OnGuard), and PhaSeal meet these acceptance criteria and can therefore all be qualified as CSTDs, but the ChemoClave system does not and so would not qualify as a CSTD.