المؤلفون: De Zwart, Loeckie, Snoeys, Jan, Jacobs, Frank, Li, Lilian Y., Poggesi, Italo, Verboven, Peter, Goris, Ivo, Scheers, Ellen, Wynant, Inneke, Monshouwer, Mario, Mamidi, Rao N. V. S.

المساهمون: Janssen Research and Development

المصدر: CPT: Pharmacometrics & Systems Pharmacology ; volume 10, issue 9, page 1107-1118 ; ISSN 2163-8306 2163-8306

الوصف: Erdafitinib is a potent oral pan‐fibroblast growth factor receptor inhibitor being developed as oncology drug for patients with alterations in the fibroblast growth factor receptor pathway. Erdafitinib binds preferentially to α1‐acid glycoprotein (AGP) and is primarily metabolized by cytochrome P450 (CYP) 2C9 and 3A4. This article describes a physiologically based pharmacokinetic (PBPK) model for erdafitinib to assess the drug–drug interaction (DDI) potential of CYP3A4 and CYP2C9 inhibitors and CYP3A4/CYP2C9 inducers on erdafitinib pharmacokinetics (PK) in patients with cancer exhibiting higher AGP levels and in populations with different CYP2C9 genotypes. Erdafitinib's DDI potential as a perpetrator for transporter inhibition and for time‐dependent inhibition and/or induction of CYP3A was also evaluated. The PBPK model incorporated input parameters from various in vitro and clinical PK studies, and the model was verified using a clinical DDI study with itraconazole and fluconazole. Erdafitinib clearance in the PBPK model consisted of multiple pathways (CYP2C9/3A4, renal, intestinal; additional hepatic clearance), making the compound less susceptible to DDIs. In poor‐metabolizing CYP2C9 populations carrying the CYP2C9*3/*3 genotype, simulations shown clinically relevant increase in erdafitinib plasma concentrations. Simulated luminal and enterocyte concentration showed potential risk of P‐glycoprotein inhibition with erdafitinib in the first 5 h after dosing, and simulations showed this interaction can be avoided by staggering erdafitinib and digoxin dosing. Other than a simulated ~ 60% exposure reduction with strong CYP3A/2C inducers such as rifampicin, other DDI liabilities were minimal and considered not clinically relevant.

الإتاحة: https://doi.org/10.1002/psp4.12682Test

المؤلفون: Saad, Fred, Chi, Kim N., Shore, Neal D., Graff, Julie N., Posadas, Edwin M., Lattouf, Jean-Baptiste, Espina, Byron M., Zhu, Eugene, Yu, Alex, Hazra, Anasuya, De Meulder, Marc, Mamidi, Rao N. V. S., Bradic, Branislav, Francis, Peter, Hayreh, Vinny, Rezazadeh Kalebasty, Arash

المساهمون: Janssen Research and Development

المصدر: Cancer Chemotherapy and Pharmacology ; volume 88, issue 1, page 25-37 ; ISSN 0344-5704 1432-0843

مصطلحات موضوعية: Pharmacology (medical), Cancer Research, Pharmacology, Toxicology, Oncology

الوصف: Purpose To assess the safety and pharmacokinetics and determine the recommended phase 2 dose (RP2D) of niraparib with apalutamide or abiraterone acetate plus prednisone (AAP) in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods BEDIVERE was a multicenter, open-label, phase 1b study of niraparib 200 or 300 mg/day with apalutamide 240 mg or AAP (abiraterone acetate 1000 mg; prednisone 10 mg). Patients with mCRPC were previously treated with ≥ 2 lines of systemic therapy, including ≥ 1 androgen receptor-axis-targeted therapy for prostate cancer. Results Thirty-three patients were enrolled (niraparib-apalutamide, 6; niraparib-AAP, 27). No dose-limiting toxicities (DLTs) were reported when combinations included niraparib 200 mg; five patients receiving niraparib 300 mg experienced DLTs [niraparib-apalutamide, 2/3 patients (66.7%); niraparib-AAP, 3/8 patients (37.5%)]. Although data are limited, niraparib exposures were lower when given with apalutamide compared with historical niraparib monotherapy exposures in patients with solid tumors. Because of the higher incidence of DLTs, the niraparib–apalutamide combination and niraparib 300 mg combination with AAP were not further evaluated. Niraparib 200 mg was selected as the RP2D with AAP. Of 19 patients receiving niraparib 200 mg with AAP, 12 (63.2%) had grade 3/4 treatment-emergent adverse events, the most common being thrombocytopenia (26.3%) and hypertension (21.1%). Five patients (26.3%) had adverse events leading to treatment discontinuation. Conclusions These results support the choice of niraparib 200 mg as the RP2D with AAP. The niraparib–AAP combination was tolerable in patients with mCRPC, with no new safety signals. An ongoing phase 3 study is further assessing this combination in patients with mCRPC. Trial registration no. NCT02924766 (ClinicalTrials.gov).

الإتاحة: https://doi.org/10.1007/s00280-021-04249-7Test

المؤلفون: Mamidi, Rao N. V. S., Dallas, Shannon, Sensenhauser, Carlo, Lim, Heng Keang, Scheers, Ellen, Verboven, Peter, Cuyckens, Filip, Leclercq, Laurent, Evans, David C., Kelley, Michael F., Johnson, Mark D., Snoeys, Jan

المصدر: British Journal of Clinical Pharmacology ; volume 83, issue 5, page 1082-1096 ; ISSN 0306-5251 1365-2125

الوصف: Aims Canagliflozin is a recently approved drug for use in the treatment of type 2 diabetes. The potential for canagliflozin to cause clinical drug–drug interactions (DDIs) was assessed. Methods DDI potential of canagliflozin was investigated using in vitro test systems containing drug metabolizing enzymes or transporters. Basic predictive approaches were applied to determine potential interactions in vivo . A physiologically‐based pharmacokinetic (PBPK) model was developed and clinical DDI simulations were performed to determine the likelihood of cytochrome P450 (CYP) inhibition by canagliflozin. Results Canagliflozin was primarily metabolized by uridine 5′‐diphospho‐glucuronosyltransferase 1A9 and 2B4 enzymes. Canagliflozin was a substrate of efflux transporters (P‐glycoprotein, breast cancer resistance protein and multidrug resistance‐associated protein‐2) but was not a substrate of uptake transporters (organic anion transporter polypeptide isoforms OATP1B1, OATP1B3, organic anion transporters OAT1 and OAT3, and organic cationic transporters OCT1, and OCT2). In inhibition assays, canagliflozin was shown to be a weak in vitro inhibitor (IC 50 ) of CYP3A4 (27 μmol l –1 , standard error [SE] 4.9), CYP2C9 (80 μmol l –1 , SE 8.1), CYP2B6 (16 μmol l –1 , SE 2.1), CYP2C8 (75 μmol l –1 , SE 6.4), P‐glycoprotein (19.3 μmol l –1 , SE 7.2), and multidrug resistance‐associated protein‐2 (21.5 μmol l –1 , SE 3.1). Basic models recommended in DDI guidelines (US Food & Drug Administration and European Medicines Agency) predicted moderate to low likelihood of interaction for these CYPs and efflux transporters. PBPK DDI simulations of canagliflozin with CYP probe substrates (simvastatin, S‐warfarin, bupropion, repaglinide) did not show relevant interaction in humans since mean areas under the concentration‐time curve and maximum plasma concentration ratios for probe substrates with and without canagliflozin and its 95% CIs were within 0.80–1.25. Conclusions In vitro DDI followed by a predictive or PBPK approach was applied ...

الإتاحة: https://doi.org/10.1111/bcp.13186Test

المؤلفون: Scheers, Ellen, Borgmans, Carine, Keung, Chi, Bohets, Hilde, Wynant, Inneke, Poggesi, Italo, Cuyckens, Filip, Leclercq, Laurent, Mamidi, Rao N. V. S.

المصدر: Xenobiotica ; volume 51, issue 2, page 177-193 ; ISSN 0049-8254 1366-5928

الإتاحة: https://doi.org/10.1080/00498254.2020.1821123Test

المؤلفون: Poggesi, Italo, Li, Lilian Y., Jiao, James, Hellemans, Peter, Rasschaert, Freya, de Zwart, Loeckie, Snoeys, Jan, De Meulder, Marc, Mamidi, Rao N. V. S., Ouellet, Daniele

المساهمون: Janssen Research and Development

المصدر: European Journal of Drug Metabolism and Pharmacokinetics ; volume 45, issue 1, page 101-111 ; ISSN 0378-7966 2107-0180

مصطلحات موضوعية: Pharmacology (medical), Pharmacology

الإتاحة: https://doi.org/10.1007/s13318-019-00581-9Test

المؤلفون: Scheers, Ellen, Borgmans, Carine, Keung, Chi, Bohets, Hilde, Wynant, Inneke, Poggesi, Italo, Cuyckens, Filip, Leclercq, Laurent, Mamidi, Rao N. V. S.

المصدر: Xenobiotica; Feb2021, Vol. 51 Issue 2, p177-193, 17p

مصطلحات موضوعية: PROTEIN-tyrosine kinase inhibitors, PSYCHONEUROIMMUNOLOGY, BILE, DOGS, RATS, METABOLISM, HUMAN beings

مستخلص: This article describes in vivo biotransformation and disposition of erdafitinib following single oral dose of ³H-erdafitinib and ¹⁴C-erdafitinib to intact and bile duct-cannulated (BC) rats (4 mg/kg), ³H-erdafitinib to intact dogs (0.25 mg/kg), and ¹⁴C-erdafitinib to humans (12 mg; NCT02692677). Peak plasma concentrations of total radioactivity were achieved rapidly (Tmax: animals, 1 h; humans, 2–3 h). Recovery of drug-derived radioactivity was significantly slower in humans (87%, 384 h) versus animals (rats: 91–98%, 48 h; dogs: 81%, 72 h). Faeces was the primary route of elimination in intact rats (95%), dogs (76%), and humans (69%); and bile in BC rats (48%). Renal elimination of radioactivity was relatively low in animals (2–12%) versus humans (19%). Unchanged erdafitinib was major component in human excreta (faeces, 17%; urine, 11%) relative to animals. M6 (O-desmethyl) was the major faecal metabolite in humans (24%) and rats (intact, 46%; BC, 11%), and M2 (O-glucuronide of M6) was the prevalent biliary metabolite in rats (14%). In dogs, besides M6, majority of radioactive dose in faeces was composed of multiple minor metabolites. In humans, unchanged erdafitinib was the major circulating entity. O-demethylation of erdafitinib was the major metabolic pathway in humans and animals. [ABSTRACT FROM AUTHOR]

: Copyright of Xenobiotica is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Poggesi, Italo, Li, Lilian Y., Jiao, James, Hellemans, Peter, Rasschaert, Freya, de Zwart, Loeckie, Snoeys, Jan, De Meulder, Marc, Mamidi, Rao N. V. S., Ouellet, Daniele

المصدر: European Journal of Drug Metabolism & Pharmacokinetics; Feb2020, Vol. 45 Issue 1, p101-111, 11p

مستخلص: Background and Objectives: Erdafitinib, an oral selective pan-fibroblast growth factor receptor (FGFR) kinase inhibitor, is primarily metabolized by cytochrome P450 (CYP) 2C9 and 3A4. The aim of this phase 1 study was to assess the pharmacokinetics and safety of erdafitinib in healthy participants when coadministered with fluconazole (moderate CYP2C9 and CYP3A inhibitor), and itraconazole (a strong CYP3A4 and P-glycoprotein inhibitor). The effect of CYP2C9 genotype variants (*1/*1, *1/*2, *1/*3) on the pharmacokinetics of erdafitinib was also investigated. Methods: In this open-label, parallel-group, single-center study, eligible healthy adults were randomized by CYP2C9 genotype to receive Treatment A (single oral dose of erdafitinib 4 mg) on day 1, Treatment B (fluconazole 400 mg/day orally) on days 1–11, or Treatment C (itraconazole 200 mg/day orally) on days 1–11. Healthy adults randomized to Treatment B and C received a single oral 4-mg dose of erdafitinib on day 5. The pharmacokinetic parameters, including mean maximum plasma concentration (Cmax), area under the curve (AUC) from time 0 to 168 h (AUC168h), AUC from time 0 to the last quantifiable concentration (AUClast), and AUC from time 0 to infinity (AUC∞) were calculated from individual plasma concentration–time data using standard non-compartmental methods. Results: Coadministration of erdafitinib with fluconazole increased Cmax of erdafitinib by approximately 21%, AUC168h by 38%, AUClast by 49%, and AUC∞ by 48% while coadministration with itraconazole resulted in no change in erdafitinib Cmax and increased AUC168h by 20%, AUClast by 33% and AUC∞ by 34%. Erdafitinib exposure was comparable between participants with CYP2C9 *1/*2 or *1/*3 and with wild-type CYP2C9 genotype. The ratio of total amount of erdafitinib excreted in the urine (inhibited to non-inhibited) was 1.09, the ratio of total amount of excreted metabolite M6 was 1.21, and the ratio of the metabolite to parent ratio in the urine was 1.11, when coadministration of erdafitinib with itraconazole was compared with single-dose erdafitinib. Treatment-emergent adverse events (TEAEs) were generally Grade 1 or 2 in severity; the most commonly reported TEAE was headache. No safety concerns were identified with single-dose erdafitinib when administered alone and in combination with fluconazole or itraconazole in healthy adults. Conclusion: Coadministration of fluconazole or itraconazole or other moderate/strong CYP2C9 or CYP3A4 inhibitors may increase exposure to erdafitinib in healthy adults and thus may warrant erdafitinib dose reduction or use of alternative concomitant medications with no or minimal CYP2C9 or CYP3A4 inhibition potential. Trial Registration: ClinicalTrials.gov identifier number: NCT03135106. [ABSTRACT FROM AUTHOR]

: Copyright of European Journal of Drug Metabolism & Pharmacokinetics is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Francke, Stephan, Mamidi, Rao N. V. S., Solanki, Bhavna, Scheers, Ellen, Jadwin, Andrew, Favis, Reyna, Devineni, Damayanthi

المصدر: The Journal of Clinical Pharmacology ; volume 55, issue 9, page 1061-1072 ; ISSN 0091-2700 1552-4604

الوصف: O ‐glucuronidation is the major metabolic elimination pathway for canagliflozin. The objective was to identify enzymes and tissues involved in the formation of 2 major glucuronidated metabolites (M7 and M5) of canagliflozin and subsequently to assess the impact of genetic variations in these uridine diphosphate glucuronosyltransferases (UGTs) on in vivo pharmacokinetics in humans. In vitro incubations with recombinant UGTs revealed involvement of UGT1A9 and UGT2B4 in the formation of M7 and M5, respectively. Although M7 and M5 were formed in liver microsomes, only M7 was formed in kidney microsomes. Participants from 7 phase 1 studies were pooled for pharmacogenomic analyses. A total of 134 participants (mean age, 41 years; men, 63%; white, 84%) were included in the analysis. In UGT1A9*3 carriers, exposure of plasma canagliflozin (C max,ss , 11%; AUC τ,ss , 45%) increased relative to the wild type. An increase in exposure of plasma canagliflozin (C max,ss , 21%; AUC t,ss , 18%) was observed in participants with UGT2B4*2 genotype compared with UGT2B4*2 noncarriers. Metabolites further delineate the role of both enzymes. The pharmacokinetic findings in participants carrying the UGT1A9*3 and UGT2B4*2 allele implicate that UGT1A9 and UGT2B4 are involved in the metabolism of canagliflozin to M7 and M5, respectively.

الإتاحة: https://doi.org/10.1002/jcph.506Test

المؤلفون: Devineni, Damayanthi, Manitpisitkul, Prasarn, Murphy, Joseph, Skee, Donna, Wajs, Ewa, Mamidi, Rao N. V. S., Tian, Hong, Vandebosch, An, Wang, Shean‐Sheng, Verhaeghe, Tom, Stieltjes, Hans, Usiskin, Keith

المساهمون: Janssen Research and Development

المصدر: Clinical Pharmacology in Drug Development ; volume 4, issue 3, page 226-236 ; ISSN 2160-763X 2160-7648

الوصف: Drug–drug interactions between canagliflozin, a sodium glucose co‐transporter 2 inhibitor, and glyburide, metformin, and simvastatin were evaluated in three phase‐1 studies in healthy participants. In these open‐label, fixed sequence studies, participants received: Study 1‐glyburide 1.25 mg/day (Day 1), canagliflozin 200 mg/day (Days 4–8), canagliflozin with glyburide (Day 9); Study 2‐metformin 2,000 mg/day (Day 1), canagliflozin 300 mg/day (Days 4–7), metformin with canagliflozin (Day 8); Study 3‐simvastatin 40 mg/day (Day 1), canagliflozin 300 mg/day (Days 2–6), simvastatin with canagliflozin (Day 7). Pharmacokinetic parameters were assessed at prespecified intervals. Co‐administration of canagliflozin and glyburide did not affect the overall exposure (maximum plasma concentration [C max ] and area under the plasma concentration–time curve [AUC]) of glyburide and its metabolites (4‐ trans ‐hydroxy‐glyburide and 3‐ cis ‐hydroxy‐glyburide). Canagliflozin did not affect the peak concentration of metformin; however, AUC increased by 20%. Though C max and AUC were slightly increased for simvastatin (9% and 12%) and simvastatin acid (26% and 18%) following coadministration with canagliflozin, compared with simvastatin administration alone; however, no effect on active 3‐hydroxy‐3‐methyl‐glutaryl‐CoA (HMG‐CoA) reductase inhibitory activity was observed. There were no serious adverse events or hypoglycemic episodes. No drug–drug interactions were observed between canagliflozin and glyburide, metformin, or simvastatin. All treatments were well‐tolerated in healthy participants.

الإتاحة: https://doi.org/10.1002/cpdd.166Test

المؤلفون: Ways, Kirk, Johnson, Mark D., Mamidi, Rao N. V. S., Proctor, James, De Jonghe, Sandra, Louden, Calvert

المصدر: Toxicologic Pathology ; volume 43, issue 1, page 48-56 ; ISSN 0192-6233 1533-1601

مصطلحات موضوعية: Cell Biology, Toxicology, Molecular Biology, Pathology and Forensic Medicine

الوصف: Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, has been developed for the treatment of adults with type 2 diabetes mellitus (T2DM). During the phase 3 program, treatment-related pheochromocytomas, renal tubular tumors, and testicular Leydig cell tumors were reported in the 2-year rat toxicology study. Treatment-related tumors were not seen in the 2-year mouse study. A cross-functional, mechanism-based approach was undertaken to determine whether the mechanisms responsible for tumorigenesis in the rat were of relevance to humans. Based on findings from nonclinical and clinical studies, the treatment-related tumors observed in rats were not deemed to be of clinical relevance. Here, we describe the scientific and regulatory journey from learning of the 2-year rat study findings to the approval of canagliflozin for the treatment of T2DM.

الإتاحة: https://doi.org/10.1177/0192623314557179Test