A microdose cocktail containing midazolam, dabigatran etexilate, pitavastatin, rosuvastatin, and atorvastatin has been established to allow simultaneous assessment of a perpetrator impact on the most common drug metabolizing enzyme, cytochrome P450 (CYP)3A, and the major transporters organic anion-transporting polypeptides (OATP)1B, breast cancer resistance protein (BCRP), and MDR1 P-glycoprotein (P-gp). The clinical utility of these microdose cocktail probe substrates was qualified by conducting clinical drug interaction studies with three inhibitors with different in vitro inhibitory profiles (rifampin, itraconazole, and clarithromycin). Generally, the pharmacokinetic profiles of the probe substrates, in the absence and presence of the inhibitors, were comparable to their reported corresponding pharmacological doses, and/or in agreement with theoretical expectations. The exception was dabigatran, which resulted in an approximately twofold higher magnitude for microdose compared to conventional dosing, and, thus, can be used to flag a worst-case scenario for P-gp. Broader application of the microdose cocktail will facilitate a more comprehensive understanding of the roles of drug transporters in drug disposition and drug interactions.

Aims To evaluate whether the potent CYP3A4 inhibitor ketoconazole has any influence on the pharmacokinetic and electrocardiographic parameters of the antimalarial co-artemether (artemether-lumefantrine) in healthy subjects. Methods Sixteen subjects were randomized in an open-label, two period crossover design study. Subjects received a single dose of co-artemether (day 1) either alone or in combination with multiple oral doses of ketoconazole (400 mg on day 1 followed by 200 mg o.d. for 4 additional days). Serial blood samples were taken and assayed for artemether and its main active metabolite dihydroartemisinin (DHA), and lumefantrine. Results The pharmacokinetics of artemether, its metabolite DHA, and lumefantrine were influenced by the presence of ketoconazole. AUC(0, • ) was increased from 320 to 740 ng ml -1 h (ratio 2.4, 90% CI 2.00, 2.86) for artemether, from 331 to 501 ng ml -1 h (ratio 1.7, 90% CI 1.40, 1.98) for DHA, and from 207 to 333 m g ml -1 h (ratio 1.7, 90% CI 1.23, 2.21) for lumefantrine in the presence of ketoconazole. C max also increased in similar proportions for the three compounds (ratio 2.2 (90% CI 1.78, 2.83), 1.4 (90% CI 1.12, 1.74), and 1.3 (90% CI 0.96, 1.64), respectively). The terminal elimination half-life was increased for artemether (2.5 vs 1.9 h, 90% CI 1.12, 1.72) and DHA (3.1 vs 2.1 h, 90% CI 0.02, 3.36), but remained unchanged for lumefantrine (88 vs 95 h, 90% CI 0.81, 1.04). These increases in exposure to the antimalarial combination were much smaller than observed with food intake (up to 16 fold), and were not associated with increased side-effects or changes in electrocardiographic parameters. The study medications were well tolerated. Conclusions The concurrent administration of ketoconazole with co-artemether led to modest increases in artemether, DHA, and lumefantrine exposure in healthy subjects. Dose adjustment of co-artemether is probably unnecessary in falciparum malaria patients when administered in association with ketoconazole or other potent CYP3A4 inhibitors.

AimsMizoribine is an oral immunosuppressive agent approved in several countries for prevention of rejection in renal transplantation. Its therapeutic window is based on trough concentrations staying at Ն0.5 but <3 mg ml -1 . It has been postulated that as renal function returns to normal, higher doses may be needed to maintain efficacy than the current clinical dosage of 2-5 mg kg -1 day -1 . The safety, tolerability and pharmacokinetics from two clinical trials of higher-dose mizoribine treatments in healthy male volunteers are presented. MethodsForty-eight healthy White male nonsmokers participated in two randomized, doubleblind, placebo-controlled trials: 32 in a single-dose study (3, 6, 9 and 12 mg kg -1 ) and 16 in a multiple-dose study [6 mg kg -1 day -1 once daily for 5 days or twice daily (12 mg kg -1 day -1 ) for 7 days]. Standard assessments of safety, tolerability and pharmacokinetics were performed. ResultsThe safety profiles of both studies were generally unremarkable, except for elevated serum uric acid concentrations at the highest dose (12 mg kg -1 day -1 ) in the multipledose study. Orally administered mizoribine reached peak concentrations within 2-3 h and was eliminated mostly via the kidney (65-100% of dose) with a 3-h half-life. Only the 12 mg kg -1 day -1 group achieved trough concentrations that were within the therapeutic window. ConclusionsBased on the favourable safety profile and current pharmacokinetic information, a new starting dose in the 6-12 mg kg -1 day -1 range is recommended in the up to 3 months acute phase following transplantation, with dose reduction recommended only if the function of the transplanted kidney is impaired.

1‐α‐D‐(5‐Fluoro‐5‐deoxyarabinofuranosyl)‐2‐nitroimidazole (fluoroazomycin arabinoside, FAZA) 6, a putative PET imaging agent when labelled with 18F, was synthesized by fluorination of 1‐α‐D‐(2,3‐di‐O‐acetylarabinofuranosyl)‐2‐nitroimidazole 3 with DAST followed by deprotection. The C‐5′‐deuterated and tritiated analogues were prepared by NaCNBD3 or NaCNBT3 reduction of the protected C‐5′‐carbonyl intermediate 5, followed by C‐5′ fluorination and deprotection, to afford C‐5′ deuterated and C‐5′ tritiated FAZA, respectively. Preliminary in vivo biodistribution studies in a murine tumour model, and pharmacokinetic studies in rats indicated that 3H‐FAZA has biodistribution, tumour uptake and pharmacokinetic properties similar to those of 123I‐IAZA, a clinically‐proven radiopharmaceutical for SPECT‐imaging of hypoxic tissues. Copyright © 1999 John Wiley & Sons, Ltd.

ImportancePreclinical data suggest that poly(ADP-ribose) polymerase (PARP) inhibitors have synergistic activity when combined with immune checkpoint inhibitors (ICIs); however, it is unknown which tumor types or molecular subtypes may benefit from this combination.ObjectiveTo investigate responses associated with the combination of avelumab and talazoparib in different tumor types and/or molecular subtypes.Design, Setting, and ParticipantsIn this phase 1b and 2 basket nonrandomized controlled trial, patients with advanced solid tumors were enrolled in the following cohorts: non–small cell lung cancer (NSCLC); DNA damage response (DDR)–positive NSCLC; triple-negative breast cancer (TNBC); hormone receptor–positive, human epidermal growth factor receptor 2 (ERBB2)–negative, DDR-positive breast cancer; recurrent, platinum-sensitive ovarian cancer (OC); recurrent, platinum-sensitive, BRCA1/2-altered OC; urothelial cancer; metastatic castration-resistant prostate cancer (mCRPC); DDR-positive mCRPC; and BRCA1/2- or ATM-altered solid tumors. Data were analyzed between June 17, 2021, and August 6, 2021.InterventionsAll patients in phases 1b and 2 received avelumab plus talazoparib.Main Outcomes and MeasuresThe phase 1b primary end point was dose-limiting toxic effects. The phase 2 primary end point was objective response, measured as objective response rate (ORR). Secondary end points included safety, time to response, duration of response (DOR), progression-free survival, time to prostate-specific antigen progression and PSA response of 50% or greater (for mCRPC), cancer antigen 125 response (for OC), pharmacokinetics, immunogenicity, and biomarkers.ResultsA total of 223 patients (mean [SD] age, 63.2 [11.0] years; 117 [52.5%] men) were treated, including 12 patients in phase 1b and 211 patients in phase 2. The recommended phase 2 dose was avelumab 800 mg every 2 weeks plus talazoparib 1 mg once daily. In phase 2, the ORR was 18.2% (95% CI, 5.2%-40.3%) in patients with TNBC; 34.8% (95% CI, 16.4%-57.3%) in patients with HR-positive, ERBB2-negative, and DDR-positive BC; and 63.6% (95% CI, 30.8%-89.1%) in patients with platinum-sensitive, BRCA1/2-altered OC. Responses occurred more frequently in patients with BRCA1/2-altered tumors. Durable responses were observed in patients with TNBC (median [range] DOR, 11.1 [3.4-20.4] months); HR-positive, ERBB2-negative, and DDR-positive BC (median [range] DOR, 15.7 [3.9 to ≥20.6] months); and BRCA1/2-altered OC (median DOR not reached; range, 5.6 to ≥18.4 months). The most common grade 3 or greater treatment-related adverse events were anemia (75 patients [33.6%]), thrombocytopenia (48 patients [21.5%]), and neutropenia (31 patients [13.9%]).Conclusions and RelevanceThis nonrandomized controlled trial found that ORRs for avelumab plus talazoparib were comparable with those with PARP inhibitor or ICI monotherapy. Prolonged DOR in patients with TNBC; HR-positive, ERBB2-negative, and DDR-positive BC; and BRCA1/2-altered OC warrant further investigation in randomized clinical trials. These data highlight the importance of prospective patient selection in future studies of ICI and PARP-inhibitor combinations.Trial RegistrationClinicalTrials.gov Identifier: NCT03330405