Four randomized, placebo-controlled, crossover studies were conducted among 282 healthy subjects to investigate whether an interaction exists between clopidogrel (300-mg loading dose/75-mg/day maintenance dose) and the proton-pump inhibitor (PPI) omeprazole (80 mg) when they are administered simultaneously (study 1); whether the interaction, if any, can be mitigated by administering clopidogrel and omeprazole 12 h apart (study 2) or by increasing clopidogrel to 600-mg loading/150-mg/day maintenance dosing (study 3); and whether the interaction applies equally to the PPI pantoprazole (80 mg) (study 4). Relative to levels after administration of clopidogrel alone in studies 1,2,3, and 4, coadministration of PPI decreased the AUC(0-24) of the clopidogrel active metabolite H4 by 40, 47, 41, and 14% (P ≤ 0.002), respectively; increased maximal platelet aggregation (MPA) induced by 5 micromol/l adenosine diphosphate (ADP) by 8.0, 5.6, 8.1, and 4.3% (P ≤ 0.014), respectively; and increased the vasodilator-stimulated phosphoprotein phosphorylation-platelet reactivity index (VASP-PRI) by 20.7, 27.1, 19.0 (P < 0.0001), and 3.9% (P = 0.3319), respectively. The results suggest that a metabolic drug-drug interaction exists between clopidogrel and omeprazole but not between clopidogrel and pantoprazole.

A double-blind crossover study was conducted in four CYP2C19 genotype-defined metabolizer groups to assess whether increase in clopidogrel dosing can overcome reduced pharmacodynamic response in CYP2C19 poor metabolizers (PMs). Ten healthy subjects in each of four metabolizer groups were randomized to a clopidogrel regimen of a 300-mg loading dose (LD) and a 75-mg/day maintenance dose (MD) for 4 days followed by 600-mg LD and 150 mg/day MD, or vice versa. The exposure levels of clopidogrel's active metabolite H4 (clopi-H4) in PMs were 71% lower on the 75-mg/day regimen and 64% lower on the 150-mg/day regimen than the corresponding exposure levels in extensive metabolizers (EMs). In PMs, the maximal platelet aggregation (MPA) induced by adenosine diphosphate (ADP) 5 µmol/l was 10.5% lower on the 75-mg/day regimen and 7.9% lower on the 150-mg/day regimen than the corresponding values in EMs. PMs who were on the clopidogrel regimen of 600-mg LD/150 mg/day MD showed clopi-H4 exposure and MPA levels similar to those in EMs who were on the regimen of 300-mg LD/75 mg/day MD. In a pooled analysis evaluating CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A5, CYP2D6, ABCB1, and P2RY12 polymorphisms (N = 396 healthy subjects), only CYP2C19 had a significant impact on antiplatelet response. In healthy CYP2C19 PMs, a clopidogrel regimen of 600-mg LD/150 mg/day MD largely overcomes diminished clopi-H4 exposure and antiplatelet response, as assessed by MPA levels.

Summary. Platelet activation and thrombus formation play a critical role in the onset of acute coronary syndromes. Thromboxane A 2 (TxA 2 ) is among the different chemical modulators released by activated platelets. TxA 2 is considered one of the most powerful agonists for platelet activation. In addition, TxA 2 exerts a vasoconstrictor effect by serving as an agonist of the thromboxane receptor (TP) on the vascular smooth muscle cell membranes. The putative effect of TxA 2 on thrombosis is demonstrated by the clinical effectiveness of acetylsalicylic acid (ASA) in the prevention of acute coronary syndromes. Among the clinically used antiplatelet agents, clopidogrel has shown to be slightly more effective than ASA in the prevention of atherothrombotic events in patients with peripheral arterial disease, and is one of the most widely used after aspirin. The aims of the study were to study the antithrombotic effects of escalating doses of the TP-receptor antagonist, S 18886 and to compare its effects with those achieved by the administration of ASA (5 mg kg )1 day )1), and clopidogrel (3 mg kg )1 day )1). The study was undertaken at high and low shear rate conditions using the Badimon perfusion chamber in a porcine model. Antithrombotic effects were assessed as changes on platelet and fibrin(ogen) deposition. The doses of 30 and 100 lg kg )1 day )1 were selected based on a previous platelet aggregation study. S 18886 shows a dosedependent antithrombotic response. The dose of S-100 develops similar antithrombotic effects to those of clopidogrel and superior to those of aspirin. The antithrombotic effects were statistically significant at both studied shear rate conditions. Therefore, the orally active TP-receptor antagonist, S 18886, appears to be a new and effective agent to prevent atherothrombotic complications.

Intrathecal morphine has been shown to be reliable in producing analgesia in patients with intractable cancer pain. Recently, we have demonstrated that intrathecal somatostatin is as effective in the treatment of cancer pain as intrathecal morphine. This report presents 2 cases in whom analgesia could be maintained for 60 and 25 days, respectively, under continuous intrathecal infusion of somatostatin by means of infusion devices.

SAR260301 had an acceptable safety profile, but exposure sufficient to inhibit the PI3K pathway was unachievable because of rapid clearance, and clinical development was terminated. These results demonstrate the importance of PK and pharmacodynamic assessments in early drug development. Cancer 2018;124:315-24. © 2017 American Cancer Society.