Effects of Rifampicin On Pyrotinib Maleate Pharmacokinetics In Healthy Subjects

Abstract Purpose: Pyrotinib (PTN) is primarily metabolized by cytochrome P450 (CYP)3A4 isozyme. Rifampicin (RIF) is a strong CYP3A4 inducer. Thus, the effect of oral RIF on PTN pharmacokinetics (PK) was evaluated to provide dose recommendation when co-administered.Method: This phase I, open-label study investigated the effects of steady-state RIF administration on single-dose PK of PTN, in 18 healthy participants who received PTN 400 mg single doses on days 1 and 13, and were administrated with RIF 600 mg qd on days 6-16. Each dose for RIF was administrated on an empty stomach, PTN were administrated orally in the morning 30 min after the start of the standard meal. Serial PK samples for PTN were collected on day 1 and day 13. Plasma PTN PK parameters were determined with non-compartmental analysis. Geometric least-squares mean ratios (GMRs) and 90% confidence intervals (CIs) were generated by the mixed-effected model for within-subject treatment comparisons. Safety assessments were performed throughout the study.Results: Eighteen subjects were enrolled and 15 completed the study. RIF significantly reduced PTN exposure: GMRs (90 % CI) for PTN + RIF versus PTN alone were 0.04 (0.034,0.049), 0.04 (0.037,0.054), and 0.11 (0.09,0.124) for area under the curve from time zero to time of last quantifiable concentration (AUC0-t), area under the curve from time zero to infinity (AUC0-∞ ), and maximum observed plasma concentration(Cmax), respectively. PTN alone and co-administered with RIF was well tolerated.Conclusion: Concurrent administration of PTN and RIF was associated with significantly decreased systemic exposure to PTN. The findings suggest that concomitant strong CYP3A4 inducers should be avoided during PTN treatment. Concurrent administration of PTN and RIF was well tolerated.

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

Hypertension ◽

10.1161/hyp.62.suppl_1.a455 ◽

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.

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Phase I/IIa, randomized, open-label, drug-drug interaction study of trabectedin and rifampin in patients with advanced cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e13512 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e13512-e13512 ◽

Cited By ~ 1

Author(s):

Arthur P. Staddon ◽

Trilok V. Parekh ◽

Roland Elmar Knoblauch ◽

Chi Keung ◽

Apexa Bernard ◽

...

Keyword(s):

Plasma Concentration ◽

Locally Advanced ◽

Plasma Concentrations ◽

Systemic Exposure ◽

Maximum Plasma ◽

Metabolic Clearance ◽

Open Label ◽

Time Curve ◽

Elimination Half ◽

Cyp3a4 Inducer

e13512 Background: Trabectedin (Yondelis; T) is a tetrahydroisoquinoline compound initially isolated from the marine tunicate, Ecteinascidia turbinata, and currently produced synthetically. It is primarily metabolized by the cytochrome P450 (CYP)3A4 enzyme. Thus, potent inducers or inhibitors of this enzyme may alter the plasma concentrations of T. This study assessed the effects of rifampin (R), a strong CYP3A4 inducer, on the pharmacokinetics (PK) and safety of T. Methods: In this 2-way crossover study, patients (≥18 years of age) with locally advanced or metastatic disease were randomized (1:1) to receive one of the 2 treatment sequences: sequence 1: R plus T followed 28 days later by T; sequence 2: T followed 28 days later by R plus T. During each sequence, R (600 mg/day) was administered for 6 consecutive days and T (1.3 mg/m2, IV) was administered over a 3 hour infusion. Dexamethasone (20 mg, IV) was administered before T administration. PK and safety of T were evaluated with and without coadministration of R. Results: Of the 11 enrolled patients, 8 were PK evaluable. Coadministration of R with T decreased mean maximum plasma concentration (Cmax) by approximately 22% and mean area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUClast) by approximately 31% (Table 1). Coadministration of R with T also resulted in 23% shorter elimination half-life. Overall, the safety profile of T was comparable when administered alone or with R. Conclusions: In comparison with T alone, coadministration of R resulted in reduced systemic exposure of T in these 8 patients, as measured by Cmax and AUClast. The coadministration of potent inducers of CYP3A4 with T may increase the metabolic clearance of T. Clinical trial information: NCT01273480. [Table: see text]

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A phase I, open-label study of the safety and pharmacokinetics (PK) of pazopanib (P) and lapatinib (L) administered concurrently

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.3088 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 3088-3088 ◽

Cited By ~ 11

Author(s):

M. Dejonge ◽

S. Savage ◽

J. Verweij ◽

T. S. Collins ◽

F. Eskens ◽

...

Keyword(s):

Tyrosine Kinases ◽

Kinase Inhibitor ◽

Aggressive Fibromatosis ◽

Clinical Activity ◽

Concurrent Administration ◽

Open Label ◽

Once Daily ◽

Open Label Study ◽

Disease Stabilization ◽

Hair Depigmentation

3088 Background: P is a potent tyrosine kinase inhibitor of VEGF-R1, -R2, and R3, PDGF-α/β, and c-Kit. L is a potent inhibitor of ErbB1 and ErbB2 tyrosine kinases. Several lines of evidence support combined inhibition of VEGFR and Erb in the treatment of malignancies. Methods: Patients (pts) with solid tumors received P and L daily. Safety, limited PK, biomarkers, and clinical activity were evaluated. Dose escalation occurred in cohorts of 3–6 pts based on DLT. Results: Thirty-three pts received L/P doses of 750/250 (n=4), 750/500 (n=6), 1000/250 (n=3), 1000/400 (n=2), 1000/500 (n=4), 1250/250 (n=6), 1250/400 (n=5) and 1500/200 (n=3) mg once daily (qd). Preliminary mean plasma P concentrations 24 h after administration (C24) on Day 22 were ∼19 μg/mL and 23 μg/mL after administration of 250 mg and 500 mg, respectively. These values are similar to mean C24 values observed after administration of 800 mg P alone (23.1 μg/mL). Plasma L concentrations at 750 - 1500 mg qd were similar to those observed after monotherapy. The most frequent AE’s were diarrhea (Grade (G)1 n=10, G2 n=2, G3 n=3), fatigue (G1: n=7, G2 n=5, G4 n=1), nausea (G1 n=9, G2 n=2), anorexia (G1 n=8, G2 n=3), vomiting (G1 n=9), hair depigmentation (n=7), rash (G1 n=6, G2 n=1) and abdominal cramps (G1 n=3, G2 n=2, G3 n=1). Prolonged disease stabilization of > 16 wks (median 21.5 wks) occurred in 10 pts (RCC n=3, CRC n=3, GIST n=1, mesothelioma n=1, adenocarcinoma GE junction n=1, aggressive fibromatosis n=1). 3 pts (renal cancer n=2, and giant cell tumor of the bone n=1) demonstrated tumor shrinkage of < 30% (i.e. SD by RECIST). Conclusions: Concurrent administration of pazopanib and lapatinib was generally well tolerated. Coadministration of lapatinib may alter the PK of pazopanib. [Table: see text]

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Latanoprost Systemic Exposure in Pediatric and Adult Patients with Glaucoma: A Phase 1, Open-Label Study

Ophthalmology ◽

10.1016/j.ophtha.2011.03.039 ◽

2011 ◽

Vol 118 (10) ◽

pp. 2022-2027 ◽

Cited By ~ 15

Author(s):

Susan Raber ◽

Rachel Courtney ◽

Tomoko Maeda-Chubachi ◽

Brad D. Simons ◽

Sharon F. Freedman ◽

...

Keyword(s):

Phase 1 ◽

Systemic Exposure ◽

Adult Patients ◽

Open Label ◽

Open Label Study ◽

Label Study

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Drug-drug interaction (DDI) potential of oral napabucasin in healthy adults.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.142 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. 142-142

Author(s):

Xiaoshu Dai ◽

Michael D. Karol ◽

Matthew Hitron ◽

Marjie Hard ◽

Matthew T. Goulet ◽

...

Keyword(s):

Phase 1 ◽

Area Under The Curve ◽

Cancer Resistance ◽

Open Label ◽

Open Label Study ◽

Investigational Agent ◽

Cyp Enzymes ◽

Oral Midazolam ◽

Grade 3

142 Background: Napabucasin is an NQO1-bioactivatable investigational agent hypothesized to affect multiple oncogenic cellular pathways including pSTAT3 through the generation of reactive oxygen species. This phase 1 open-label study evaluated the DDI potential of napabucasin and its major metabolite (M1) with respect to 7 major human drug cytochrome P450 (CYP) enzymes and the breast cancer resistance protein (BCRP) transporter. Methods: Healthy adult subjects who initially demonstrated they could tolerate administration of 240 or 480 mg twice daily (BID) napabucasin over 2-days (D) received single doses of the CYP and transporter substrates, followed by ≥7-day washout. In the DDI portion, subjects received napabucasin 240 mg BID on D1–11 with the phenotyping cocktail administered on D6 (omeprazole [CYP2C19] 20 mg, caffeine [CYP1A2] 100 mg, flurbiprofen [CYP2C9] 50 mg, bupropion [CYP2B6] 150 mg, dextromethorphan [CYP2D6] 30 mg, and oral midazolam [CYP3A] 2 mg), intravenous (IV) midazolam 2 mg on D7, repaglinide (CYP2C8) 0.25 mg on D8, and rosuvastatin (BRCP transporter) 10 mg on D9. Results: DDI potential was evaluated in 17 subjects. Exposure to omeprazole, flurbiprofen, and oral midazolam with (test) or without (reference) napabucasin 240 mg BID were similar. Napabucasin increased exposure (area under the curve to infinity) to caffeine (124%), IV midazolam (118%), repaglinide (127%), and rosuvastatin (213%); and decreased exposure to bupropion (79%) and dextromethorphan (71%). None of these changes were expected to be clinically meaningful. The exposure of the major metabolites of the probe drugs with or without napabucasin or M1 were similar. Of the 17 subjects, 12 (70.6%) reported adverse events (AEs); 58.8% reported gastrointestinal disorders. One patient had a grade 3 AE (neutrophil count low); no serious AEs were observed. Conclusions: The data suggest minimal in vivo DDI potential for napabucasin with respect to 7 major human drug CYP enzymes and the BCRP transporter. Napabucasin 240 mg BID was generally tolerable in healthy subjects. Co-administration of napabucasin with CYP and transporter substrates was safe and tolerable. Clinical trial information: NCT03411122.

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Intrapulmonary Pharmacokinetics and Pharmacodynamics of Posaconazole at Steady State in Healthy Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00663-08 ◽

2008 ◽

Vol 53 (2) ◽

pp. 703-707 ◽

Cited By ~ 56

Author(s):

John E. Conte ◽

Jeffrey A. Golden ◽

Gopal Krishna ◽

Marina McIver ◽

Emily Little ◽

...

Keyword(s):

Area Under The Curve ◽

Healthy Adults ◽

Pharmacokinetics And Pharmacodynamics ◽

Open Label ◽

Multiple Dosing ◽

Alveolar Cell ◽

Epithelial Lining Fluid ◽

Open Label Study ◽

Dosing Interval ◽

The Mean

ABSTRACT We evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of posaconazole (POS) in a prospective, open-label study. Twenty-five healthy adults received 14 doses of POS oral suspension (400 mg twice daily) with a high-fat meal over 8 days. Pulmonary epithelial lining fluid (ELF) and alveolar cell (AC) samples were obtained via bronchoalveolar lavage, and blood samples were collected during the 24 h after the last dose. POS concentrations were determined using liquid chromatography with tandem mass spectrometry parameters. The maximum concentrations (C max) (mean ± standard deviation) in plasma, ELF, and ACs were 2.08 ± 0.93, 1.86 ± 1.30, and 87.7 ± 65.0 μg/ml. The POS concentrations in plasma, ELF, and ACs did not decrease significantly, indicating slow elimination after multiple dosing. The mean concentrations of POS in plasma, ELF, and ACs were above the MIC90 (0.5 μg/ml) for Aspergillus spp. over the 12-h dosing interval and for 24 h following the last dose. Area under the curve from 0 to 12 h (AUC0-12) ratios for ELF/plasma and AC/plasma were 0.84 and 33. AUC0-24/MIC90 ratios in plasma, ELF, and AC were 87.6, 73.2, and 2,860. Nine (36%) of 25 subjects had treatment-related adverse events during the course of the study, which were all mild or moderate. We conclude that a dose of 400 mg twice daily resulted in sustained plasma, ELF, and AC concentrations above the MIC90 for Aspergillus spp. during the dosing interval. The intrapulmonary PK/PD of POS are favorable for treatment or prevention of aspergillosis, and oral POS was well tolerated in healthy adults.

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Effect of verapamil on systemic exposure and safety of umeclidinium and vilanterol: a randomized and open-label study

International Journal of Chronic Obstructive Pulmonary Disease ◽

10.2147/copd.s40859 ◽

2013 ◽

pp. 159 ◽

Cited By ~ 22

Author(s):

Rashmi Mehta ◽

Kelleher ◽

Andrew Preece ◽

Hughes ◽

Crater

Keyword(s):

Systemic Exposure ◽

Open Label ◽

Open Label Study ◽

Label Study

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Clinical Pharmacokinetics of Oral Controlled-Release 5-Fluorocytosine

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01103-09 ◽

2009 ◽

Vol 54 (3) ◽

pp. 1237-1241 ◽

Cited By ~ 5

Author(s):

Manjunath P. Pai ◽

Hollie Bruce ◽

Linda A. Felton

Keyword(s):

Controlled Release ◽

Phase 1 ◽

Hydroxypropyl Methylcellulose ◽

Area Under The Curve ◽

Immediate Release ◽

The United States ◽

Open Label ◽

Clinical Pharmacokinetics ◽

Time Zero

ABSTRACT 5-Fluorocytosine (5FC) is an oral antifungal that is currently used in combination with amphotericin B to treat Cryptococcus neoformans meningoencephalitis. The oral dosing of 5FC could be optimized by the use of a controlled-release (CR) formulation. The objective of the current study was to develop two prototype 5FC-CR formulations and evaluate the single-dose (1,500-mg) serum pharmacokinetic profiles of those formulations relative to the profile of the commercially available, immediate-release 5FC product (Ancobon) by the use of a phase 1, open-label, randomized, three-phase, crossover pharmacokinetic study design. Hydroxypropyl methylcellulose was utilized as the rate-controlling matrix to compound the 5FC-CR tablets. The two prototype 5FC-CR formulations demonstrated 80% release at 13.0 and 18.4 h, respectively, whereas the immediate-release product demonstrated 80% release at 0.28 h, as determined in vitro by the United States Pharmacopeia apparatus 2 dissolution method. Five subjects completed all three phases of the study without any adverse events. The mean maximum concentration, the area under the curve from time zero to 24 h, and the area under the curve from time zero to infinity were approximately 50% lower (P < 0.01) with the 5FC-CR formulations than with the immediate-release 5FC product. However, no statistically significant differences in the minimum concentrations at 24 h were noted between the formulations. The gastric absorption profile of 5FC-CR was well predicted by in vitro dissolution. Future exploration of a gastroretentive 5FC-CR formulation could overcome the marked lack of bioequivalence observed in the present study.

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