scholarly journals Effect of ceritinib on the pharmacokinetics of coadministered CYP3A and 2C9 substrates: a phase I, multicenter, drug–drug interaction study in patients with ALK + advanced tumors

2021 ◽  
Author(s):  
Felipe K. Hurtado ◽  
Filippo de Braud ◽  
Javier De Castro Carpeño ◽  
Maria Jose de Miguel Luken ◽  
Ding Wang ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Phase I ◽  
Kinase Inhibitor ◽  
Geometric Mean ◽  
Concomitant Administration ◽  
Primary Objective ◽  
Adult Patients ◽  
Open Label ◽  
Drug Drug Interaction ◽  
Advanced Tumors

Abstract Purpose Ceritinib is an ALK receptor tyrosine kinase inhibitor approved as first- and second-line treatment in adult patients with ALK + metastatic non-small cell lung cancer (NSCLC). The study investigated the drug–drug interaction (DDI) potential of ceritinib when coadministered with midazolam and warfarin as probe substrates for CYP3A and CYP2C9 activity, respectively. Methods This was a phase I, multicenter, open-label, single sequence, crossover DDI study in 33 adult patients with ALK + NSCLC or other advanced tumors. A single dose of a cocktail consisting of midazolam and warfarin was administered with and without concomitant administration of ceritinib. The primary objective was to evaluate the pharmacokinetics of midazolam and warfarin. Secondary objectives included pharmacokinetics, safety, tolerability, overall response rate (ORR), and duration of response (DOR) of ceritinib 750 mg once daily. Results Ceritinib inhibited CYP3A-mediated metabolism of midazolam, resulting in a markedly increased AUC (geometric mean ratio [90% confidence interval]) by 5.4-fold (4.6, 6.3). Ceritinib also led to an increase in the AUC of S-warfarin by 54% (36%, 75%). The pharmacokinetics and safety profile of ceritinib in this study are consistent with previous reports and no new safety signals were reported. Among the 19 patients with NSCLC, efficacy (ORR: 42.1% and DCR: 63.2%) was similar to that reported previously in studies of pretreated patients with ALK + NSCLC. Conclusion Ceritinib is a strong CYP3A inhibitor and a weak CYP2C9 inhibitor. These findings should be reflected as actionable clinical recommendations in the prescribing information for ceritinib with regards to concomitant medications whose pharmacokinetics may be altered by ceritinib.

Drug–drug interaction between itraconazole capsule and efavirenz in adults with HIV for talaromycosis treatment

2020 ◽  
Author(s):  
Quanhathai Kaewpoowat ◽  
Romanee Chaiwarith ◽  
Saowaluck Yasri ◽  
Navaporn Worasilchai ◽  
Ariya Chindamporn ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Geometric Mean ◽  
Compartmental Analysis ◽  
Concomitant Administration ◽  
Open Label ◽  
Capsule Formulation ◽  
Post Dose ◽  
Cd4 Cell Count ◽  
Drug Drug Interaction ◽  
Cd4 Cell

Abstract Objectives To assess the pharmacokinetic of itraconazole capsule formulation and its active metabolite, hydroxyitraconazole, in adults with HIV diagnosed with talaromycosis in an endemic area, and to evaluate the drug–drug interaction between itraconazole/hydroxyitraconazole (ITC/OH-ITC) and efavirenz. Methods Open-label, single arm, sequential pharmacokinetic study. Eligible subjects were adults with HIV, ≥18 years old, with confirmed talaromycosis, initiating itraconazole capsule as part of standard talaromycosis treatment, in whom efavirenz-based ART was anticipated. Steady-state pharmacokinetic assessments (pre-dose and at 1, 3, 4, 5, 6, 8 and 12 h post dose) were performed for itraconazole/hydroxyitraconazole without and with efavirenz use. Mid-dose efavirenz concentrations were also assessed. Pharmacokinetics parameters were calculated using non-compartmental analysis. Results Ten subjects (70% male) were enrolled. At entry, median (range) age was 29.5 years (22–64), and CD4 cell count was 18.0 (1–39) cells/mm3. Geometric mean (95% CI) of itraconazole and hydroxyitraconazole AUC0–12 without efavirenz were 9097 (6761–12 239) and 11 705 (8586-15 959) ng·h/mL, respectively, with a median metabolic ratio of OH-ITC : ITC of 1.3 (95% CI 0.9–1.9). Intra-subject comparison revealed that both itraconazole and hydroxyitraconazole exposures were significantly reduced with concomitant efavirenz use, with the mean AUC0–12 of itraconazole and hydroxyitraconazole being 86% (71%–94%) and 84% (64%–97%) lower, respectively. With efavirenz, itraconazole trough concentrations were also below the recommended therapeutic level (0.5 μg/mL). All subjects had mid-dose efavirenz concentrations >1000 ng/mL. Conclusions Concomitant administration of itraconazole capsule with efavirenz significantly reduced itraconazole and hydroxyitraconazole exposures. The clinical impact of this drug–drug interaction on talaromycosis treatment or prophylaxis in the era of potent ART needs further evaluation.

scholarly journals A phase 1, open-label, drug–drug interaction study of rucaparib with rosuvastatin and oral contraceptives in patients with advanced solid tumors

2021 ◽  
Author(s):  
Mingxiang Liao ◽  
Krzysztof G. Jeziorski ◽  
Monika Tomaszewska-Kiecana ◽  
István Láng ◽  
Marek Jasiówka ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Solid Tumors ◽  
Oral Contraceptives ◽  
Interaction Analysis ◽  
Phase 1 ◽  
Geometric Mean ◽  
Pharmacokinetic Analysis ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Drug Drug Interaction

Abstract Purpose This study aimed at evaluating the effect of rucaparib on the pharmacokinetics of rosuvastatin and oral contraceptives in patients with advanced solid tumors and the safety of rucaparib with and without coadministration of rosuvastatin or oral contraceptives. Methods Patients received single doses of oral rosuvastatin 20 mg (Arm A) or oral contraceptives ethinylestradiol 30 µg + levonorgestrel 150 µg (Arm B) on days 1 and 19 and continuous doses of rucaparib 600 mg BID from day 5 to 23. Serial blood samples were collected with and without rucaparib for pharmacokinetic analysis. Results Thirty-six patients (n = 18 each arm) were enrolled and received at least 1 dose of study drug. In the drug–drug interaction analysis (n = 15 each arm), the geometric mean ratio (GMR) of maximum concentration (Cmax) with and without rucaparib was 1.29 for rosuvastatin, 1.09 for ethinylestradiol, and 1.19 for levonorgestrel. GMR of area under the concentration–time curve from time zero to last quantifiable measurement (AUC0–last) was 1.34 for rosuvastatin, 1.43 for ethinylestradiol, and 1.56 for levonorgestrel. There was no increase in frequency of treatment-emergent adverse events (TEAEs) when rucaparib was given with either of the probe drugs. In both arms, most TEAEs were mild in severity and considered unrelated to study treatment. Conclusion Rucaparib 600 mg BID weakly increased the plasma exposure to rosuvastatin or oral contraceptives. Rucaparib safety profile when coadministered with rosuvastatin or oral contraceptives was consistent with that of rucaparib monotherapy. Dose adjustments of rosuvastatin and oral contraceptives are not necessary when coadministered with rucaparib. ClinicalTrials.gov NCT03954366; Date of registration May 17, 2019.

Abstract 455: Assessment of Pharmacokinetic Drug-drug Interaction between LCZ696 and Hydrochlorothiazide

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Hsiu-Ling Hsiao ◽  
Michael Greeley ◽  
Parasar Pal ◽  
Thomas Langenickel ◽  
Gangadhar Sunkara ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Upper Bound ◽  
Healthy Subjects ◽  
Geometric Mean ◽  
Systemic Exposure ◽  
Compartmental Analysis ◽  
Angiotensin Receptor ◽  
Open Label ◽  
Neprilysin Inhibitor ◽  
Drug Drug Interaction

Objective: LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) being developed for the treatment of cardiovascular diseases, including hypertension and heart failure. Ingestion of LCZ696 results in systemic exposure to AHU377 (inactive prodrug of LBQ657, a neprilysin inhibitor) and valsartan (angiotensin receptor blocker). Hydrochlorothiazide (HCTZ) is indicated as first line treatment of hypertension. Since LCZ696 and HCTZ may be co-administered for optimal blood pressure control, this study was conducted to evaluate the pharmacokinetic (PK) drug-drug interaction potential between LCZ696 and HCTZ. Methods: An open-label, three-period, single sequence study in 27 healthy subjects was conducted. In Period 1, subjects received oral HCTZ 25 mg qd x 4 days and were discharged for a 4-10 day washout. In Period 2, subjects received LCZ696 400 mg qd x 5 days, and in Period 3, HCTZ 25 mg qd + LCZ696 400 mg qd x 4 days. Serial PK samples were collected and analyzed by a validated LC-MS/MS method. PK parameters (AUCtau,ss,Cmax,ss) of LCZ696 analytes (LBQ657, valsartan) and HCTZ in plasma were determined using non-compartmental analysis, and the results were statisticallyevaluated. Results: The 90% CIs confidence intervals (CIs) for the geometric mean ratio for AUCtau,ss of HCTZ fell within the ( 0.8 - 1.25) range, while those of Cmax,ss (0.74, 0.70-0.78) fell outside the range, indicating Cmax,ss of HCTZ decreased by 26% when co-administered with LCZ696. Those for AUCtau,ss of LBQ657 fell within the range but the upper bound for Cmax,ss (1.19, 1.10-1.28) was outside the range, indicating Cmax of LBQ657 increased by 19%; the upper bound for valsartan exposures(AUCtau,ss: 1.14, 1.00-1.29; Cmax,ss: 1.16, 0.98-1.37) were above the range, indicating AUCtau,ss and Cmax,ss of valsartan increased by 14%and 16%, respectively. Conclusion: When LCZ696 400mg qd and HCTZ 25mg qd were co- administered, AUCtau,ss of HCTZ was unchanged but Cmax,ss decreased by 26%; AUCtau,ss of LBQ657 was unchanged but Cmax,ss increased by 19%; and lastly, AUCtau,ss and Cmax,ss of valsartan increased by 14%and 16%, respectively. LCZ696 400 mg qd was safe and well tolerated in healthy subjects when administered alone and in combination with HCTZ 25 mg qd.

A phase I study determining the safety and tolerability of combination therapy with pazopanib, a VEGFR/PDGFR/raf inhibitor, and GSK1120212, a MEK inhibitor, in advanced solid tumors enriched with patients with advanced differentiated thyroid cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS3117-TPS3117 ◽  
Author(s):  
Shabina Roohi Ahmed ◽  
Nilofer Saba Azad ◽  
Douglas Wilmot Ball ◽  
Michelle A. Rudek ◽  
Barry Nelkin ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Phase I ◽  
Differentiated Thyroid Cancer ◽  
Kinase Inhibitor ◽  
Performance Status ◽  
Critical Role ◽  
Growth Factor Receptor ◽  
Primary Objective ◽  
Open Label ◽  
Expansion Cohort

TPS3117 Background: Mutations of the RAS/RAF/MEK/ERK signaling pathway, especially RAS, BRAF and IGF-I/II receptor genes play a critical role in the development of many different types of cancers, including breast, colorectal, melanoma, NSCLC, and thyroid. Differentiated thyroid cancer (DTC) is the most common endocrine malignancy, but there is currently no approved therapy for advanced radioiodine-resistant disease. In DTC xenograft models, vertical inhibition of this pathway, achieved by targeting the vascular endothelial growth factor receptor (VEGFR) and MEK, has shown greater clinical efficacy than with either agent alone. Pazopanib (P) is a small molecule tyrosine kinase inhibitor that selectively inhibits VEGFR1-3, PDGFR-α, PDGFR-b, c-kit, and FGFR 1-3. Phase II data in advanced DTC from Bible, et al, indicate a 49% response rate with a PFS of 11.7 months in a patients with PD within 6 months. GSK1120212 (G) is a potent, highly selective, allosteric inhibitor of MEK1/2. In a phase I/II study, Infante et al. reported an ORR of 81% in BRAF mutant melanoma patients when G was combined with a RAF inhibitor. Methods: A phase I, open label, dose escalation trial with P+G is currently accruing pts with advanced malignancies. The study is a standard 3+3 design with an expansion cohort of 25 pts with advanced DTC for correlative endpoints and PK studies. Pts will be treated with P at 400 mg QD, 600 mg QD and 800 mg QD, with G held constant at 1 mg QD; G will then be escalated to 1.5 mg QD and 2 mg QD. Eligibility includes advanced solid tumor, good end organ function and performance status, and PD within 6 months in the expansion cohort. The primary objective is to determine the safety and tolerability of the combination and determine the MTD. Secondary objectives include assessing preliminary efficacy as defined by RECIST criteria and PFS, and exploration of PK/PD endpoints. Serial tumor biopsies will be evaluated for changes in signaling through p-ERK. RAS and RAF mutation sites will be sequenced in order to correlate with PD endpoints and disease response. Currently, DL1 has accrued with no DLTs.

scholarly journals No relevant pharmacokinetic drug–drug interaction between nintedanib and pirfenidone

2018 ◽  
Vol 53 (1) ◽  
pp. 1801060 ◽  
Author(s):  
Luca Richeldi ◽  
Sophie Fletcher ◽  
Huzaifa Adamali ◽  
Nazia Chaudhuri ◽  
Sabrina Wiebe ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Plasma Concentration ◽  
Geometric Mean ◽  
Maximum Plasma ◽  
Open Label ◽  
Time Curve ◽  
Drug Drug Interaction ◽  
Group 2 ◽  
Pharmacokinetic Drug ◽  
Group 1

Nintedanib and pirfenidone are approved treatments for idiopathic pulmonary fibrosis (IPF). This open-label, two-group trial investigated the pharmacokinetic drug–drug interaction between these two drugs in patients with IPF.Subjects not treated with antifibrotics at screening (group 1, n=20) received a single nintedanib dose (150 mg) followed by pirfenidone (titrated to 801 mg thrice daily) for 3 weeks, with a further single nintedanib dose (150 mg) on the last day (day 23). Subjects treated with pirfenidone at screening (group 2, n=17) continued to receive pirfenidone alone (801 mg thrice daily) for 7 days, then co-administered with nintedanib (150 mg twice daily) for a further 7 days, before single doses of both treatments on day 16.In group 1, adjusted geometric mean (gMean) ratios (with/without pirfenidone) were 88.6% and 80.6% for nintedanib area under the plasma concentration–time curve (AUC) and maximum plasma concentration (Cmax), respectively. In group 2, gMean ratios (with/without nintedanib) were 97.2% and 99.5% for pirfenidone AUC and Cmax, respectively. For all parameters, the 90% confidence intervals included 100%, suggesting similar exposure for administration alone and when co-administered. Both treatments were well tolerated.These data indicate there is no relevant pharmacokinetic drug–drug interaction between nintedanib and pirfenidone when co-administered in IPF patients.

Effect of high-dose rifampicin on efavirenz pharmacokinetics: drug–drug interaction randomized trial

2020 ◽  
Vol 75 (5) ◽  
pp. 1250-1258
Author(s):  
Daniel Atwine ◽  
Elisabeth Baudin ◽  
Thibaut Gelé ◽  
Winnie Muyindike ◽  
Kenneth Mworozi ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Randomized Trial ◽  
Geometric Mean ◽  
High Dose ◽  
Open Label ◽  
Art Initiation ◽  
Tb Treatment ◽  
Open Label Phase ◽  
Drug Drug Interaction ◽  
Hiv 1

Abstract Background High-dose rifampicin is considered to shorten anti-TB treatment duration but its effect on antiretroviral metabolism is unknown. Objectives To assess the effect of doubling the rifampicin dose (to 20 mg/kg/day, R20) on efavirenz pharmacokinetics (PK) in HIV/TB coinfected patients. Methods Open-label Phase 2 drug–drug interaction randomized trial. Pulmonary TB, ART-naive adults were randomized to R20 and either efavirenz 600 mg (EFV600) or 800 mg (EFV800), or rifampicin 10 mg/kg/day (R10) and EFV600 with a 1:1:1 ratio. Patients were first started on TB treatment and 2–4 weeks later started on ART. They were switched to R10 and EFV600 after 8 weeks. Full PK sampling was done 4 weeks (on rifampicin) and 24 weeks (off rifampicin) after ART initiation. Transaminases, plasma HIV-1 RNA and sputum cultures were monitored. The efavirenz geometric mean ratio (GMR) of AUC at 4 and 24 weeks after ART initiation within the same patient was calculated in each arm and its 90% CI was compared with a preset range (0.70–1.43). Results Of 98 enrolled patients (32 in the R20EFV600 arm, 33 in the R20EFV800 arm and 33 in the R10EFV600 arm), 87 had full PK sampling. For the R20EFV600, R20EFV800 and R10EFV600 arms, GMRs of efavirenz AUC were 0.87 (90% CI: 0.75–1.00), 1.12 (90% CI: 0.96–1.30) and 0.96 (90% CI: 0.84–1.10). Twelve weeks after ART initiation, 78.6%, 77.4% and 72.4% of patients had HIV-1 RNA below 100 copies/mL and 85.7%, 86.7% and 80.0% had Week 8 culture conversion, respectively. Two patients per arm experienced a severe increase in transaminases. Conclusions Doubling the rifampicin dose had a small effect on efavirenz concentrations and was well tolerated.

Abstract 457: Assessment of Pharmacokinetic Drug-drug Interaction between LCZ696 and Carvedilol

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Hsiu-Ling Hsiao ◽  
Michael Greeley ◽  
Parasar Pal ◽  
Thomas Langenickel ◽  
Gangadhar Sunkara ◽  
...  
Keyword(s):  
Heart Failure ◽  
Drug Interaction ◽  
Healthy Subjects ◽  
Geometric Mean ◽  
Systemic Exposure ◽  
Angiotensin Receptor ◽  
Open Label ◽  
Risk Of Death ◽  
Neprilysin Inhibitor ◽  
Drug Drug Interaction

Objective: LCZ696 is a first-in-class angiotensin receptor neprlysin inhibitor (ARNI) being developed for the treatment of hypertension and heart failure. Ingestion of LCZ696 results in systemic exposure to AHU377 (inactive prodrug of LBQ657, a neprilysin inhibitor) and valsartan (angiotensin receptor blocker). Carvedilol is a third-generation, non-selective beta-blocker with vasodilating properties and one of three beta-blockers with efficacy in reducing the risk of death in patients with heart failure. Since LCZ696 may be co-administered with carvedilol for optimal blood pressure control, this study was conducted to evaluate the pharmacokinetic (PK) drug-drug interaction potential between LCZ696 and carvedilol. Methods: An open-label, three-period, single sequence study in 28 healthy subjects was conducted. In Period 1, subjects received oral LCZ696 400 mg qd x 5 days and were discharged for a 4-10 day washout. In Period 2, subjects received oral carvedilol 12.5 mg bid x first 2 days, then 25 mg bid x 4 days, and in Period 3, LCZ696 400 mg qd + carvedilol 25 mg bid x 5 days. Serial PK samples were collected and analyzed by a validated LC-MS/MS method. PK parameters (AUCtau,ss, Cmax,ss) of LCZ696 analytes(LBQ657, valsartan) and carvedilol (R(+)-and S(-)-carvedilol) in plasma were determined using non-compartmental analysis, and results were statistically evaluated. Results: The 90% CIs of the geometric mean ratio for AUCtau,ss and Cmax,ss of LBQ657, and AUCtau,ss of valsartan fell within the range of (0.80-1.25); the lower bound for Cmax,ss of valsartan (0.88, 0.78-0.98) was below the range, indicating PK of LBQ567 was not altered but Cmax,ss of valsartan decreased by 12% when co-administered with carvedilol. Those for AUCtau,ss and Cmax,ss of both R(+)-and S(-)carvedilol fell within the range (0.80-1.25), indicating no change in PK of Carvedilol in combination with LCZ696. Conclusion: When LCZ696 400 mg qd and carvedilol 25 mg bid were co-dministered, PK of carvedilol (R(+)-and S(-)-carvedilol) was unchanged. PK of LBQ657 or AUCtau,ss of valsartan was unchanged, while Cmax,ss decreased by 12%. LCZ696 400 mg qd was safe and well tolerated in healthy subjects when administered alone and in combination with carvedilol 25 mg bid.

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