Real-World Evaluation of Dosing in Patients Converted From Insulin Glargine (Lantus) to Insulin Glargine (Basaglar).

Background: Basaglar, insulin glargine (BGlar; Eli Lilly, Indianapolis, IN), a follow-on biologic, was developed after the patent for Lantus, insulin glargine (LGlar; Sanofi-Aventis, Paris, France) expired. Objective: To compare the dosing and hemoglobin A1C (A1C)-lowering effects of BGlar compared with LGlar in a real-world setting. Methods: Adult patients, at 5 clinics, with type 1 (T1DM) or type 2 diabetes mellitus (T2DM) who were converted from LGlar to BGlar were included in this retrospective observational study. The primary outcome compared mean basal insulin dose (U/d) from the date of conversion to 6 months. Basal insulin and total daily insulin doses were also compared from baseline to 3- and 12-months postconversion, as also change in A1C, body weight, and estimated monthly acquisition costs of basal insulin. Results: Of the 225 patients included, 56% were male, and 81% had T2DM. The mean conversion dose (U/d) of LGlar was 46.3 ± 32.7. There was no significant difference in the mean BGlar dose (U/d) at 6 months (45.9 ± 33.5; P = 0.52), nor was there a statistical difference at 3 or 12 months. There were no significant differences in change in A1C at any time point. The estimated monthly acquisition cost of BGlar was significantly less than that for LGlar at conversion ($286 vs $341, P < 0.001) and 6 months ($290 vs $351, P < 0.001) respectively. Conclusion/Relevance: The results of this retrospective study suggest that BGlar resulted in similar glycemic outcomes compared with LGlar in a real-world setting and may be a preferable option in a value-based health care environment.

In vitro evaluation of the inhibition and induction potential of olaparib, a potent poly(ADP-ribose) polymerase inhibitor, on cytochrome P450.

1. In vitro studies were conducted to evaluate potential inhibitory and inductive effects of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, on cytochrome P450 (CYP) enzymes. Inhibitory effects were determined in human liver microsomes (HLM); inductive effects were evaluated in cultured human hepatocytes. 2. Olaparib did not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2D6 or CYP2E1 and caused slight inhibition of CYP2C9, CYP2C19 and CYP3A4/5 in HLM up to a concentration of 100 µM. However, olaparib (17-500 µM) inhibited CYP3A4/5 with an IC50 of 119 µM. In time-dependent CYP inhibition assays, olaparib (10 µM) had no effect against CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1 and a minor effect against CYP3A4/5. In a further study, olaparib (2-200 µM) functioned as a time-dependent inhibitor of CYP3A4/5 (KI, 72.2 µM and Kinact, 0.0675 min-1). Assessment of the CYP induction potential of olaparib (0.061-44 µM) showed minor concentration-related increases in CYP1A2 and more marked increases in CYP2B6 and CYP3A4 mRNA, compared with positive control activity; however, no significant change in CYP3A4/5 enzyme activity was observed. 3. Clinically significant drug-drug interactions due to olaparib inhibition or induction of hepatic or intestinal CYP3A4/5 cannot be excluded. It is recommended that olaparib is given with caution with narrow therapeutic range or sensitive CYP3A substrates, and that prescribers are aware that olaparib may reduce exposure to substrates of CYP2B6.

In vitro assessment of the roles of drug transporters in the disposition and drug-drug interaction potential of olaparib.

1. In vitro assessments were conducted to examine interactions between olaparib (a potent oral inhibitor of poly[ADP-ribose] polymerase) and drug transporters. 2. Olaparib showed inhibition of the hepatic drug uptake transporters OATP1B1 (IC50 values of 20.3 µM and 27.1 µM) and OCT1 (IC50 37.9 µM), but limited inhibition of OATP1B3 (25% at 100 µM); inhibition of the renal uptake transporters OCT2 (IC50 19.9 µM) and OAT3 (IC50 18.4 µM), but limited inhibition of OAT1 (13.5% at 100 µM); inhibition of the renal efflux transporters MATE1 and MATE2K (IC50s 5.50 µM and 47.1 µM, respectively); inhibition of the efflux transporter MDR1 (IC50 76.0 µM), but limited inhibition of BCRP (47% at 100 µM) and no inhibition of MRP2. At clinically relevant exposures, olaparib has the potential to cause pharmacokinetic interactions via inhibition of OCT1, OCT2, OATP1B1, OAT3, MATE1 and MATE2K in the liver and kidney, as well as MDR1 in the liver and GI tract. Olaparib was found to be a substrate of MDR1 but not of several other transporters. 3. Our assessments indicate that olaparib is a substrate of MDR1 and may cause clinically meaningful inhibition of MDR1, OCT1, OCT2, OATP1B1, OAT3, MATE1 and MATE2K.

Pharmacokinetics, safety, and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial.

BACKGROUND: The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib potentiated radiation and temozolomide (TMZ) chemotherapy in preclinical glioblastoma models but brain penetration was poor. Clinically, PARP inhibitors exacerbate the hematological side effects of TMZ. The OPARATIC trial was conducted to measure penetration of recurrent glioblastoma by olaparib and assess the safety and tolerability of its combination with TMZ. METHODS: Preclinical pharmacokinetic studies evaluated olaparib tissue distribution in rats and tumor-bearing mice. Adult patients with recurrent glioblastoma received various doses and schedules of olaparib and low-dose TMZ in a 3 + 3 design. Suitable patients received olaparib prior to neurosurgical resection; olaparib concentrations in plasma, tumor core and tumor margin specimens were measured by mass spectrometry. A dose expansion cohort tested tolerability and efficacy of the recommended phase II dose (RP2D). Radiosensitizing effects of olaparib were measured by clonogenic survival in glioblastoma cell lines. RESULTS: Olaparib was a substrate for multidrug resistance protein 1 and showed no brain penetration in rats but was detected in orthotopic glioblastoma xenografts. Clinically, olaparib was detected in 71/71 tumor core specimens (27 patients; median, 496 nM) and 21/21 tumor margin specimens (9 patients; median, 512.3 nM). Olaparib exacerbated TMZ-related hematological toxicity, necessitating intermittent dosing. RP2D was olaparib 150 mg (3 days/week) with TMZ 75 mg/m2 daily for 42 days. Fourteen (36%) of 39 evaluable patients were progression free at 6 months. Olaparib radiosensitized 6 glioblastoma cell lines at clinically relevant concentrations of 100 and 500 nM. CONCLUSION: Olaparib reliably penetrates recurrent glioblastoma at radiosensitizing concentrations, supporting further clinical development and highlighting the need for better preclinical models.

Clinical Pharmacokinetics and Pharmacodynamics of Cediranib.

Cediranib potently and selectively inhibits all three vascular endothelial growth factor receptors (VEGFR-1, -2 and -3), and clinical studies have shown that it is effective in patients with ovarian cancer at a dose of 20 mg/day. Cediranib is absorbed moderately slowly; a high-fat meal reduced the cediranib area under the plasma concentration-time curve (AUC) by 24% and maximum plasma concentration (C max) by 33%. Cediranib binds to serum albumin and α1-acid glycoprotein; protein binding in human plasma is approximately 95%. The cediranib AUC and C max increase proportionally with dose from 0.5 to 60 mg, and cediranib has linear pharmacokinetics (PK) over time. Cediranib is metabolized via flavin-containing monooxygenase 1 and 3 (FMO1, FMO3) and uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A4. Cediranib and its metabolites are mainly excreted in faeces (59%), with <1% of unchanged drug being excreted in urine. The apparent oral clearance is moderate and the mean terminal half-life is 22 h. Cediranib is a substrate of multidrug resistance-1 (MDR1) protein (also known as P-glycoprotein [P-gp]). Coadministration with ketoconazole, a potent P-gp inhibitor, increases cediranib AUC at steady-state (AUCss) in patients by 21%, while coadministration with rifampicin, a potent inducer of P-gp, decreases cediranib AUCss by 39%. Administration of cediranib with chemotherapies demonstrated minimal PK impact on each other. No dose adjustment is recommended for patients with mild or moderate hepatic or renal impairment, and no dose adjustment is needed on the basis of age and body weight. A pooled analysis at doses of 0.5-60 mg showed no significant increase in QTc intervals. Increases in blood pressure and the incidence of diarrhoea were associated with increased cediranib dose and systemic exposure.