Disposition and Metabolism of Darapladib, a Lipoprotein-Associated Phospholipase A2 Inhibitor, in Humans

Abstract

The absorption, metabolism, and excretion of darapladib, a novel inhibitor of lipoprotein-associated phospholipase A 2 , was investigated in healthy male subjects using [14 C]-radiolabeled material in a bespoke study design. Disposition of darapladib was compared following single i.v. and both single and repeated oral administrations. The anticipated presence of low circulating concentrations of drug-related material required the use of accelerator mass spectrometry as a sensitive radiodetector. Blood, urine, and feces were collected up to 21 days post radioactive dose, and analyzed for drug-related material. The principal circulating drug-related component was unchanged darapladib. No notable metabolites were observed in plasma post-i.v. dosing; however, metabolites resulting from hydroxylation (M3) and N-deethylation (M4) were observed (at 4%-6% of plasma radioactivity) following oral dosing, indicative of some first-pass metabolism. In addition, an acidcatalyzed degradant (M10) resulting from presystemic hydrolysis was also detected in plasma at similar levels of ∼5% of radioactivity post oral dosing. Systemic exposure to radioactive material was reduced within the repeat dose regimen, consistent with the notion of time-dependent pharmacokinetics resulting from enhanced clearance or reduced absorption. Elimination of drug-related material occurred predominantly via the feces, with unchanged darapladib representing 43%-53% of the radioactive dose, and metabolites M3 and M4 also notably accounting for ∼9% and 19% of the dose, respectively. The enhanced study design has provided an increased understanding of the absorption, distribution, metabolism and excretion (ADME) properties of darapladib in humans, and substantially influenced future work on the compound.

The pharmacokinetics and safety of darapladib in subjects with severe renal impairment

“…This study evaluated the effects of severe renal impairment, compared with normal renal function, on the pharmacokinetics and safety/tolerability of oral repeat dosing of darapladib. Although a human radiolabel study had previously shown that less than 0.5% of the administered darapladib dose is eliminated by the renal route , severe renal impairment resulted in considerable reduction in darapladib overall clearance in total and unbound darapladib as well as in all three metabolites. Exposure increase was most pronounced in unbound darapladib exposure which is the entity presumably responsible for the pharmacological and toxicological actions of darapladib.…”

“…In addition to CYP3A, darapladib is also a substrate for P‐glycoprotein . Studies have shown conflicting effects of uraemia on P‐glycoprotein activity in the intestine, kidney and liver .…”

“…Elimination of darapladib occurs primarily by hepatic metabolism as unchanged parent compound and renal excretion represents less than 0.5% of the administered dose. Although darapladib is extensively metabolized in the liver, with metabolites primarily excreted though the faeces , renal impairment can affect its systemic exposure through various mechanisms . Accumulating evidence has shown that renal impairment can lead to alterations in non‐renal clearance by affecting drug metabolizing enzymes and transporters .…”

Human absorption, distribution, metabolism and excretion properties of drug molecules: a plethora of approaches

“…In order to gain an insight into the possible mechanisms behind this disparity, the relative disposition and metabolism of radiolabelled drug was compared at steady‐state and after single oral and i.v. doses of 14 C‐drug . The design of the steady‐state arm of the study was such that a single radiolabelled dose was administered on day 11 during the 14 day repeat oral dosing of non‐labelled drug.…”

Single and Multiple Dose Pharmacokinetics, Pharmacodynamics and Safety of the Novel Lipoprotein-Associated Phospholipase A2 Enzyme Inhibitor Darapladib in Healthy Chinese Subjects: An Open Label Phase-1 Clinical Trial

“…According to the biopharmaceutical classification system (BCS), darapladib is considered to be a Class 4 substance due to its low passive permeability (≤7 nm/s at pH 5.5) and low solubility (>1, 0.8, 0.3 and <0.1 mg/mL at pH 2, 4, 6 and 8, respectively) [Unpublished data]. Consistent with Class 4 BCS products, the absolute bioavailability of oral darapladib is low (4% for darapladib enteric coated tablet [Unpublished data] and 12% for a solution [ 6 ]). Compared with the fasted state, administration of a high fat meal with darapladib enteric coated tablet resulted in a 19% increase in systemic exposure (AUC) to darapladib and the higher exposure is not considered to be clinically relevant [Unpublished data].…”