Addition of the 3-series fatty acid precursor (icosapentaenoic acid, IPA), its endoperoxide [prostaglandin (PG) H3J, or thromboxane A3 to human platelet-rich plasma (PRP) does not result in aggregation of the platelets. In fact, preincubation of human PRP with exogenous PGH3 actually inhibited aggregation by increasing platelet cyclic AMP concentrations. PGH3 undergoes rapid spontaneous degradation to PGD3 in human PRP. The PGD3 so formed is adequate to account for the increase of platelet cAMP and inhibition of aggregation. Furthermore, addition of PGD-specific antisera to human PRP blocked the platelet inhibitory activity of exogenous PGH3. PGD3 has considerable potential as a circulating antithrombotic agent. Pretreatment of human PRP with the adenylate cyclase inhibitor 2',5'-dideoxyadenosine blocked the increase of platelet cyclic AMP and the inhibition of aggregation normally produced by PGI2, PGE1, PGD2, PGH3, and PGD3. Furthermore, the dideoxyadenosine unmasked a direct but moderate reversible aggregatory effect in response to the subsequent addition of PGH3. Similarly, the dideoxyadenosine markedly enhanced the aggregation produced by exogenous PGH2. IPA is readily incorporated into tissue lipids but proved to be a poor substrate for kidney, blood vessel, or heart cyclooxygenase. IPA was previously shown to be a poor substrate for platelet cyclooxygenase. IPA is readily deacylated from the renal phospholipid pool in response to bradykinin, a substance that aso stimulates the release of arachidonic acid. A diet that relies primarily on cold-water fish, as in the case of the Greenland Eskimos, lowers endogenous arachidonic acid and markedly increases the IPA content of tissue lipids. Thus, because IPA has the potential to act as an antagonist with arachidonic acid for platelet cyclooxygenase and lipoxygenase, the simultaneous release of IPA could suppress any residual arachidonic acid conversion to its aggregatory metabolites. The normal 2-series prostaglandin (PG) family is derived from arachidonic acid (AA; 5,8,11,14-icosatetraenoic acid). AA and its metabolites PGH2 and thromboxane A2 are potent stimulators of platelet aggregation. The fatty acid precursor of the 3-series PG family, 5,8,11,14,17-icosapentaenoic acid (IPA), can be enzymatically converted by sheep cyclooxygenase into the PG endoperoxide PGH3 (1, 2). Purified PGH3 in turn is converted by the appropriate enzyme source into thromboxane A3 or A'7-prostacyclin (PGI3) (2). The 3-series endoperoxide and thromboxane are less potent contractile agents on rabbit thoracic aorta strips than the corresponding 2-series compounds (i.e., PGH2 and thromboxane A2) (1), and similarly PGI3 relaxes isolated coronary arterial strips but is less potent than PGI2 (3). Surprisingly, the 3-series fatty acid (IPA), endoperoxide (PGH3), and thromboxane (thromboxane A3) do not induce aggregation in human platelet-rich-plasma (PRP) (1) and, furthermore, preincubation of human PRP with exogenous PGH3 or The publication costs of this article were defrayed i...

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Purpose GSK2982772 is a selective inhibitor of receptor-interacting protein kinase-1, with a 2–3 h half-life. This study evaluated if a once-daily modified-release formulation of GSK2982772 could be developed with no significant food effect. Methods Part A evaluated the pharmacokinetics of GSK2982772 following fasted single-dose (120 mg) administration of two matrix minitab formulations (MT-8 h and MT-12 h) vs 120 mg immediate release (IR) and MT-12 h with a high-fat meal. Part B evaluated once-daily MT-12 h for 3 days at three dose levels. Part C evaluated a matrix monolithic (MM-12 h) formulation at two dose levels in different prandial states. Results All modified-release formulations dosed in the fasted state reduced maximum plasma concentration (Cmax), delayed time to Cmax, and decreased area under the curve (AUC) vs IR. When MT-12 h or MM-12 h were co-administered with a meal (standard or high-fat) Cmax and AUC increased. Dosing MM-12 h 1 h before a standard or high-fat meal had minimal impact on exposure vs fasted. Conclusions MT-12 h and MM-12 h provided a QD pharmacokinetic profile in the fasted state, however when MT-12 h was dosed with a high-fat meal a QD profile was not maintained. (ClinicalTrials.gov Identifier: NCT03266172).

Purpose GSK2982772 is a selective inhibitor of receptor-interacting protein kinase-1 (RIPK1) with a short 2- to 3-h half-life. In a previous modified-release (MR) study, a matrix monolithic formulation (80% GSK2982772 released over 12 h) provided a once-daily (QD) pharmacokinetic (PK) profile in the fasted state; however, it was susceptible to food effects. The current study evaluated the safety and PK of MR formulations using GSK proprietary DiffCORE™ technology. Methods Part A evaluated PK following single-dose (240 mg) fasted and fed (high-fat meal) administration of three DiffCORE MR formulations within pre-defined in vitro extremes of 80% GSK2982772 released over 12 h (MR-12 h) to 80% GSK2982772 released over 18 h (MR-18 h) versus an immediate-release formulation. Part B evaluated MR-16 h (120–960 mg) in different prandial states. Results Pharmacokinetic profiles for all MR formulations and doses tested in the fasted and fed states were consistent with QD dosing. Conclusions The DiffCORE technology overcame the food effect vulnerability observed with the matrix monolithic formulation. The MR-16 h formulation was selected for further clinical development as a QD dosing regimen (NCT03649412 September 26, 2018).