Impact of Drug Pressure versus Limited Access to Drug in Malaria Control: The Dilemma

Malaria burden has severe impact on the world. Several arsenals, including the use of antimalarials, are in place to curb the malaria burden. However, the application of these antimalarials has two extremes, limited access to drug and drug pressure, which may have similar impact on malaria control, leading to treatment failure through divergent mechanisms. Limited access to drugs ensures that patients do not get the right doses of the antimalarials in order to have an effective plasma concentration to kill the malaria parasites, which leads to treatment failure and overall reduction in malaria control via increased transmission rate. On the other hand, drug pressure can lead to the selection of drug resistance phenotypes in a subpopulation of the malaria parasites as they mutate in order to adapt. This also leads to a reduction in malaria control. Addressing these extremes in antimalarial application can be essential in maintaining the relevance of the conventional antimalarials in winning the war against malaria.

Improving the Solubility, Dissolution, and Bioavailability of Metronidazole via Cocrystallization with Ethyl Gallate

Metronidazole (MTZ) is an antibacterial drug widely used for the treatment of protozoan and anaerobic infections in humans and animals. However, its low bioavailability necessitates the frequent administration of a high dose to attain an effective plasma concentration profile for therapy. To reduce the dose of MTZ, we have prepared a new cocrystal between MTZ and ethyl gallate (EG). The solid-state properties of MTZ-EG were characterized using complimentary techniques, including thermal, spectroscopic, microscopic, and X-ray crystallographic methods. The MTZ-EG cocrystal exhibits a higher solubility and faster dissolution than MTZ. The bioavailability of MTZ in rats was increased by 36% when MTZ-EG was used.

Transdermal Fentanyl Uptake at Two Different Patch Locations in Swiss White Alpine Sheep

When using animals in biomedical research, investigators have the responsibility to ensure adequate analgesia. Currently, transdermal fentanyl patches (TFP) are often used to provide postoperative analgesia in large laboratory animals. The aim of this study was to compare the fentanyl uptake resulting from TFP applied at two different locations, namely the foreleg and the thorax, in healthy adult sheep. Twelve sheep received a TFP with an intended dosage of 2 ug/kg/h. Blood samples were taken at different time points over a period of five days and the fentanyl plasma levels were measured. The TFP applied on the foreleg allowed a faster fentanyl uptake with higher peaks and a longer time within or above the target concentration of 0.6–1.5 ng/mL, shown to be analgesic in humans, when compared to the one on the thorax. Assuming that the effective plasma concentration described for humans is providing analgesia in sheep as well, the present findings suggest that it should be sufficient to apply the TFP 3–6 h before the painful insult and that its effect should last at least 48 h. Furthermore, when TFP are used to provide postoperative analgesia in sheep, they should be placed on the foreleg rather than on the thorax.

Pharmacokinetics of Salicylic Acid Following Intravenous and Oral Administration of Sodium Salicylate in Sheep

The pharmacokinetics of salicylic acid (SA) in sheep was evaluated following intravenous (IV) and oral administration of sodium salicylate (sodium salt of salicylic acid) at different doses. Six healthy sheep were administered sodium salicylate (SS) IV at doses of 10, 50, 100 and 200 mg/kg body weight and another six sheep were drenched with 100 and 200 mg/kg of SS orally. Both studies were randomised crossover trials. A one-week washout period between each treatment was allowed in both studies. Blood samples were collected at 0, 15, 30 min and 1, 2, 4 and 6 h after IV and oral SS administrations. Plasma SA concentrations were determined using high-performance liquid chromatography (HPLC) with diode array detection method. Pharmacokinetic variables were calculated in a non-compartmental model. The elimination half-life (T1/2 el) of SA after IV administration of 200 mg/kg SS was 1.16 ± 0.32 h. Mean bioavailability of SA was 64%, and mean T1/2 el was 1.90 ± 0.35 h, after 200 mg/kg of oral SS. The minimum plasma SA concentration (16.8 µg/mL) reported to produce analgesia in humans was achieved after IV administration of 100 and 200 mg/kg SS in sheep for about 0.17 h in this study. Experiments on pharmacokinetic–pharmacodynamics modelling are required to determine the actual effective plasma concentration range of SA in sheep.

Pharmacokinetics of Salicylic Acid Following Intravenous and Oral Administration of Sodium Salicylate in Sheep

The pharmacokinetics of salicylic acid (SA) in sheep was evaluated following intravenous (IV) and oral administration of sodium salicylate (sodium salt of salicylic acid) at different doses. Six healthy sheep were administered sodium salicylate (SS) IV at doses of 10, 50, 100 and 200 mg/kg body weight and another six sheep were drenched with 100 and 200 mg/kg of SS orally. Both studies were randomised crossover trials. A one-week washout period between each treatment was allowed in both studies. Blood samples were collected at 0, 15, 30 minutes and 1, 2, 4 and 6 hours after IV and oral SS administrations. Plasma SA concentrations were determined using high performance liquid chromatography with diode array detection method. Pharmacokinetic variables were calculated in a non-compartmental model. The elimination half-life (T1/2 el) of SA after IV administration of 200 mg/kg SS was 1.16 ± 0.32 hours. Mean bioavailability of SA was 64%, and mean T1/2 el was 1.90 ± 0.35 hours, after 200 mg/kg of oral SS. The minimum plasma SA concentration (16.8 µg/mL) required to produce analgesia in humans was achieved after IV administration of 100 and 200 mg/kg SS in sheep for about 0.17 hour in this study. Experiments on pharmacokinetic-pharmacodynamics modelling are required to determine the actual effective plasma concentration range of SA in sheep.

Comprehensive Analysis Of The In Vitro Potency Of Ponatinib, and All Other Approved BCR-ABL Tyrosine Kinase Inhibitors (TKIs), Against a Panel Of Single and Compound BCR-ABL Mutants

Background Secondary mutations in BCR-ABL are the most common cause of resistance to TKIs in patients (pts) with chronic myeloid leukemia (CML). Ponatinib is a potent pan-BCR-ABL TKI that has been shown to suppress the emergence of any single mutation in vitro, including T315I, at clinically achievable concentrations (40 nM), though higher concentrations were required to suppress emergence of certain compound mutations (2 mutations in the same BCR-ABL allele). Ponatinib has demonstrated significant clinical activity in pts in the phase 2 PACE trial, 60% of whom received 3 or more prior TKIs. Responses were observed for each of the 15 mutations present in >1 chronic phase CML pt at baseline, and no single mutation conferring resistance to ponatinib has emerged to date, though in some cases development of compound mutations has been observed. To gain a more precise understanding of the effects of specific mutations on the clinical efficacy of ponatinib, IC50s for ponatinib, and all other approved TKIs, against 31 single or compound BCR-ABL mutants were determined. To explore the relationship between in vitro potency and clinical efficacy, IC50s were related to “effective” TKI levels achieved in patients. Methods TKI potency was assessed in engineered Ba/F3 cells by measuring cell viability at 72 hours. The effective plasma concentration for each TKI was calculated from published average steady-state concentration values for the recommended dose, and adjusted for the functional effects of protein binding. These effects were assessed by determining the degree to which TKI potency was reduced by the presence of physiological concentrations of human serum albumin (HSA) and alpha 1-acid glycoprotein (AAG). Results The activity of ponatinib, and 5 other TKIs, against 21 single BCR-ABL mutants is shown in Figure A. Ponatinib potently inhibited viability of native BCR-ABL and all mutants, including T315I (IC50s (nM): 3-16). The IC50s for the other TKIs, excluding T315I (>4000 for all) ranged from: 201-10,000 (imatinib), 12-784 (nilotinib), 2-104 (dasatinib), 40-1,280 (bosutinib) and 18-5,216 (radotinib). IC50 values were compared to the effective plasma concentration for each TKI (Figure A). Mutants that have previously been associated with clinical resistance to a particular TKI tended to have IC50s that approached or substantially exceeded the effective concentration for that TKI, including most mutants for imatinib, E255K/V, Y253H, L248R, T315I for nilotinib, and V299L, F317C/I/V, T315A/I for dasatinib. The most problematic mutants for bosutinib predicted by this analysis were F317V, L248R, V299L, and T315I. Notably, all mutant IC50s fell below the effective concentration for ponatinib. The activity of all TKIs against 10 clinically-observed BCR-ABL compound mutants was also assessed. Four compound mutants had IC50s near or above the effective concentration for ponatinib (T315I+M351T, E255V+F317I, T315I+E255K, T315I+E255V) (Figure B). All 4, plus others, are also predicted to be problematic for the other TKIs. Conclusions Relating in vitro TKI potency to “effective” steady-state plasma concentrations in patients identified mutations known to confer clinical resistance to imatinib, nilotinib and dasatinib. This method of analysis suggests that ponatinib may be able to inhibit all single BCR-ABL mutants, but not all compound mutants, a prediction that is thus far consistent with results observed in patients. Compound mutations that are predicted to confer resistance to ponatinib are also predicted to confer resistance to all other approved TKIs. Early introduction of ponatinib may prevent the emergence of single mutations, and thus the sequential development of compound mutations. Disclosures: Gozgit: ARIAD: Employment, Equity Ownership. Schrock:ARIAD: Employment, Equity Ownership. Chen:ARIAD: Employment, Equity Ownership. Clackson:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Rivera:ARIAD: Employment.