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1.
Clin Drug Investig ; 37(2): 195-205, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27785737

ABSTRACT

BACKGROUND AND OBJECTIVES: Entospletinib is a selective, reversible, adenosine triphosphate-competitive small-molecule spleen tyrosine kinase (SYK) inhibitor that blocks B cell receptor-mediated signaling and proliferation in B lymphocytes. This study evaluated the safety, pharmacokinetics, and pharmacodynamics of entospletinib in a double-blind, single/multiple ascending dose study in healthy volunteers. METHODS: In sequential cohorts, 120 subjects received entospletinib (25-1200 mg; fasted) as single or twice-daily oral doses for 7 days. Along with pharmacokinetics, the study assessed functional inhibition of ex vivo anti-immunoglobulin E-stimulated CD63 expression on basophils and pervanadate-evoked phosphorylated SYK (pSYK) Y525. Safety and tolerability were assessed throughout the study. RESULTS: Entospletinib was generally well-tolerated over a 48-fold dose range. Adverse events (AEs) were generally mild to moderate, with no AE-driven study drug discontinuations noted. Entospletinib displayed a median plasma half-life of 9-15 h; entospletinib exposures reached a plateau at ≥600 mg twice daily (likely due to solubility-limited absorption) and provided >90% CD63 inhibition at peak concentrations and >60% inhibition at trough concentrations (corresponding pSYK inhibition of >70 and >50%). CONCLUSION: The overall safety, pharmacokinetics, and pharmacodynamics profiles of entospletinib support further clinical evaluation.


Subject(s)
Syk Kinase/antagonists & inhibitors , Adolescent , Adult , B-Lymphocytes/drug effects , Basophils/drug effects , Cohort Studies , Dose-Response Relationship, Drug , Double-Blind Method , Female , Food-Drug Interactions , Healthy Volunteers , Humans , Male , Middle Aged , Tetraspanin 30/biosynthesis , Tetraspanin 30/drug effects , Vanadates/pharmacology , Young Adult
2.
J Clin Pharmacol ; 55(8): 944-52, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25821156

ABSTRACT

Idelalisib, a phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, is metabolized primarily by aldehyde oxidase to form GS-563117, an inactive metabolite, and is metabolized to a lesser extent by cytochrome P450 3A and uridine 5'-diphospho-glucuronosyltransferase 1A4. In a mass balance study, the orally administered idelalisib dose was recovered mainly in feces (∼78%). This study evaluated the pharmacokinetics and safety of a single 150-mg dose of idelalisib in subjects with moderate or severe hepatic impairment and in age-, sex-, and weight-matched, healthy controls. The idelalisib maximum observed plasma concentration was generally comparable in subjects with moderate or severe hepatic impairment versus healthy controls, whereas the mean area under the curve was higher (58% to 59%). GS-563117 exposures were lower in impaired versus healthy control subjects, likely because of lower formation in the setting of liver impairment. Exploratory analyses indicated no relevant relationships between idelalisib or GS-563117 plasma exposures and Child-Pugh-Turcotte scores. Single oral doses of idelalisib 150 mg were well tolerated, with most treatment-emergent adverse events (AEs) and laboratory abnormalities being grades 1 or 2 in severity. As such, no dose adjustment was required when initiating idelalisib treatment in patients with mild or moderate hepatic impairment, although close monitoring for potential AEs is recommended.


Subject(s)
Antineoplastic Agents/pharmacokinetics , Liver Diseases/metabolism , Protein Kinase Inhibitors/pharmacokinetics , Purines/pharmacokinetics , Quinazolinones/pharmacokinetics , Adult , Aged , Antineoplastic Agents/adverse effects , Female , Humans , Male , Middle Aged , Protein Binding , Protein Kinase Inhibitors/adverse effects , Purines/adverse effects , Quinazolinones/adverse effects
3.
J Clin Pharmacol ; 55(8): 909-19, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25760671

ABSTRACT

Idelalisib, a potent phosphatidylinositol-3-kinase delta (PI3Kδ) inhibitor, is metabolized primarily by aldehyde oxidase to form GS-563117 and to a lesser extent by cytochrome P450 (CYP) 3A and uridine 5'-diphospho-glucuronosyltransferase 1A4. In vitro, idelalisib inhibits P-glycoprotein (P-gp) and organic anion transporting polypeptides 1B1 and 1B3, and GS-563117 is a time-dependent CYP3A inhibitor. This study enrolled 24 healthy subjects and evaluated (1) the effect of idelalisib on the pharmacokinetics (PK) of digoxin, a P-gp probe substrate, rosuvastatin, a breast cancer resistance protein, and OATP1B1/OATP1B3 substrate, and midazolam, a CYP3A substrate; and (2) the effect of a strong inducer, rifampin, on idelalisib PK. On treatment, the most common clinical adverse events (AEs) were headache and pyrexia. Grade 3 transaminase increases were observed in 5 of 24 subjects and were reversible. Two subjects had serious AEs after treatment completion (grade 3 pyrexia and/or drug-induced liver injury). Idelalisib coadministration did not affect digoxin and rosuvastatin PK. Coadministration with idelalisib increased plasma exposures of midazolam (138% and 437% for maximum observed plasma concentration [Cmax ] and area under the plasma concentration-time curve from time 0 extrapolated to infinity [AUCinf ], respectively), consistent with the in vitro finding of CYP3A inhibition by GS-563117. Rifampin caused a substantial decrease in idelalisib (58% and 75%, Cmax and AUCinf , respectively) and GS-563117 exposures, indicating an enhanced contribution of CYP3A to idelalisib metabolism under a strongly induced state.


Subject(s)
Antineoplastic Agents/pharmacology , Antineoplastic Agents/pharmacokinetics , Purines/pharmacology , Purines/pharmacokinetics , Quinazolinones/pharmacology , Quinazolinones/pharmacokinetics , Adult , Antineoplastic Agents/blood , Digoxin/blood , Digoxin/pharmacokinetics , Drug Interactions , Female , Healthy Volunteers , Humans , Male , Midazolam/blood , Midazolam/pharmacokinetics , Middle Aged , Phosphoinositide-3 Kinase Inhibitors , Purines/blood , Quinazolinones/blood , Rifampin/pharmacology , Rosuvastatin Calcium/blood , Rosuvastatin Calcium/pharmacokinetics , Young Adult
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