Publications by authors named "Reza Khosravan"

Drug-drug interaction (DDI) is an important consideration for clinical decision making in prostate cancer treatment. The objective of this study was to evaluate the effect of enzalutamide, an oral androgen receptor inhibitor, on the pharmacokinetics (PK) of digoxin (P-glycoprotein [P-gp] probe substrate) and rosuvastatin (breast cancer resistance protein [BCRP] probe substrate) in men with metastatic castration-resistant prostate cancer (mCRPC). This was a phase I, open-label, fixed-sequence, crossover study (NCT04094519).

View Article and Find Full Text PDF
Article Synopsis
  • A population pharmacokinetic study analyzed the behavior of sunitinib and its active metabolite SU012662 in children with gastrointestinal stromal tumors (GIST) to determine appropriate dosing compared to adults.
  • Using data from 65 children, researchers employed nonlinear mixed-effects modeling to develop pharmacokinetic models, confirming that body surface area (BSA) significantly impacted the drug's parameters.
  • The findings suggest that a sunitinib dose of approximately 20 mg/m²/day in children would achieve plasma exposure levels similar to a 50 mg/day dose in adults, highlighting the importance of customizing treatment based on individual characteristics like BSA.
View Article and Find Full Text PDF

Purpose: The starting dose of sunitinib in children with gastrointestinal stromal tumors (GIST) was extrapolated based on data in adults with GIST or solid tumors and children with solid tumors.

Methods: Integrated population pharmacokinetics (PK), PK/pharmacodynamics (PD), and exposure-response analyses using nonlinear mixed-effects modeling approaches were performed to extrapolate PK and PD of sunitinib in children with GIST at projected dose(s) with plasma drug exposures comparable to 50-mg/day in adults with GIST. The analysis datasets included PK/PD data in adults with GIST and adults and children with solid tumors.

View Article and Find Full Text PDF
Article Synopsis
  • The study investigated the safety profile of sunitinib, a cancer drug, in children with solid tumors, analyzing how drug exposure affects various safety endpoints.
  • It involved data from 59 children aged 2-21 and examined factors that could influence the drug's pharmacokinetics (PK) and pharmacodynamics (PD) using a nonlinear mixed-effects model.
  • The results showed that body surface area (BSA) significantly affected drug clearance and distribution, and higher sunitinib concentrations were linked to an increased likelihood of adverse effects, with no other demographic factors influencing this relationship.
View Article and Find Full Text PDF

Using physiologically based pharmacokinetic (PBPK) modeling and simulations, this study estimated the exposure of sunitinib and its active metabolite SU012662 in pediatric patients. A PBPK simulator, SimCYP, was used to develop and validate the pharmacokinetic models. Model development employed a combined "bottom-up" and "top-down" approach to fully utilize the available in vitro or in silico experimental data and in vivo observed clinical data.

View Article and Find Full Text PDF

Background: Sunitinib is approved for treatment of adults with imatinib-resistant gastrointestinal stromal tumor (GIST) or imatinib intolerance.

Methods: This single-arm, multicenter, multinational phase I/II clinical trial (NCT01396148) enrolled eligible patients aged 6 to < 18 years with advanced, unresectable GIST with non-mutant KIT, or who demonstrated disease progression or intolerance to imatinib. Patients received sunitinib 15 mg/m per day, 4-weeks-on/2-weeks-off (schedule 4/2), for ≤ 18 cycles over 24 months.

View Article and Find Full Text PDF

Background: In a phase III study, sunitinib led to a significant increase in progression-free survival (PFS) versus placebo in patients with pancreatic neuroendocrine tumours (panNETs). This study was a post-marketing commitment to support the phase III data.

Methods: In this ongoing, open-label, phase IV trial (NCT01525550), patients with progressive, advanced unresectable/metastatic, well-differentiated panNETs received continuous sunitinib 37.

View Article and Find Full Text PDF

Purpose: We assessed the effect of baseline patient demographic and disease characteristics on the crizotinib pharmacokinetic parameters oral clearance (CL/F), volume of distribution (V2/F), and area under the curve at steady state (AUC) following multiple crizotinib 250-mg twice-daily dosing in patients with ALK-positive cancer.

Experimental Design: A pharmacokinetic model was fit to data from 1,214 patients. We identified statistically significant covariates (P ≤ 0.

View Article and Find Full Text PDF

Background: Sunitinib is a multi-targeted tyrosine kinase inhibitor used in the treatment of advanced renal cell carcinoma (RCC) and imatinib-resistant/intolerant gastrointestinal stromal tumors (GIST).

Methods: A meta-analysis of 10 prospective clinical studies in advanced RCC and GIST was performed to support the development of pharmacokinetic (PK) and PK/pharmacodynamic (PD) models that account for the effects of important covariates. These models were used to make predictions with respect to the PK, safety, and efficacy of sunitinib when administered on the traditional 4-weeks-on/2-weeks-off schedule (Schedule 4/2) versus an alternative schedule of 2 weeks on/1 week off (Schedule 2/1).

View Article and Find Full Text PDF

Background: GIST patients often undergo GI-surgery. Previous studies have shown that imatinib and nilotinib exposures were decreased in GIST patients with prior major gastrectomy. We investigated whether major gastrectomy influences the exposure to sunitinib and its active metabolite SU12662.

View Article and Find Full Text PDF

Background: This phase II study evaluated the efficacy and safety/tolerability of sunitinib plus trastuzumab in patients with HER2-positive advanced breast cancer (ABC).

Methods: Eligible patients received sunitinib 37.5 mg/day and trastuzumab administered either weekly (loading, 4 mg/kg; then weekly 2 mg/kg) or 3-weekly (loading, 8 mg/kg; then 3-weekly 6 mg/kg).

View Article and Find Full Text PDF

Purpose: This randomized, open-label phase II study compared the efficacy of sunitinib monotherapy with that of single-agent standard-of-care (SOC) chemotherapy in patients with previously treated advanced triple-negative breast cancer (TNBC).

Methods: Patients with advanced TNBC, relapsed after anthracycline- and taxane-based chemotherapy, were randomized to receive either sunitinib (37.5 mg/day) or the investigator's choice of SOC therapy.

View Article and Find Full Text PDF

What Is Already Known About This Subject: Hyperuricaemia and gout frequently coexist with cardiovascular disorders such as hypertension and heart failure. The use of diuretics has been re-established as a first-line treatment for patients with hypertension and the effects of diuretics on serum uric acid may diminish the urate-lowering effects of febuxostat, a novel, potent, non-purine selective inhibitor of xanthine oxidase.

What This Study Adds: Co-administration of febuxostat 80 mg and hydrochlorothiazide 50 mg had no effect on the pharmacokinetics and did not have a clinically significant effect on the pharmacodynamics of febuxostat.

View Article and Find Full Text PDF

Absorption, metabolism, and excretion of one 80 mg oral dose of [(14)C] febuxostat ([thiazole-4-(14)C] 2-[3-cyano-4-isobutoxyphenyl]-4-methyl-5-thiazolecarboxylic acid) were studied in 6 healthy subjects. Mean cumulative recovery in excreta was 94% (49% urine and 45% feces) of the dose over 9 days; 87% of the dose was profiled. Seventeen radioactive peaks were observed in urine and fecal chromatograms.

View Article and Find Full Text PDF

This phase I, open-label, single-dose study evaluates the effects of severe renal impairment and end-stage renal disease (ESRD) requiring hemodialysis on the pharmacokinetics, safety, and tolerability of sunitinib and its primary active metabolite, SU12662. Subjects with normal renal function (creatinine clearance > 80 mL/min), severe renal impairment (creatinine clearance < 30 mL/min), and ESRD requiring hemodialysis receive a single dose of sunitinib 50 mg. Serial blood samples are collected for quantification of plasma concentrations using a validated liquid chromatography with tandem mass spectrometry assay.

View Article and Find Full Text PDF

Febuxostat is a novel nonpurine selective inhibitor of xanthine oxidase, which is currently being developed for the management of hyperuricemia in patients with gout. The effect of age and gender on the pharmacokinetics, pharmacodynamics, and safety of once-daily oral febuxostat 80 mg was assessed in healthy male and female subjects after 7 days. Following multiple dosing with febuxostat, there were no statistically significant differences in the plasma or urinary pharmacokinetic or pharmacodynamic parameters between subjects aged 18 to 40 years and >or=65 years.

View Article and Find Full Text PDF

Unlabelled: What is already known about this subject. Febuxostat is a novel nonpurine selective inhibitor of xanthine oxidase. What this study adds.

View Article and Find Full Text PDF

Background: Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase currently being developed for the management of hyperuricemia in patients with gout.

Objective: To investigate the pharmacokinetics, pharmacodynamics and safety of febuxostat over a range of oral doses in healthy subjects.

Methods: In a phase I, dose-escalation study, febuxostat was studied in dose groups (10, 20, 30, 40, 50, 70, 90, 120, 160, 180 and 240 mg) of 12 subjects each (10 febuxostat plus 2 placebo).

View Article and Find Full Text PDF

To evaluate the effect of febuxostat on the pharmacokinetics of indomethacin and naproxen and vice versa, 2 multiple-dose, 3-period crossover studies were performed in healthy subjects. In study 1, subjects received febuxostat 80 mg once daily, indomethacin 50 mg twice daily, or both. In study 2, subjects received febuxostat 80 mg, naproxen 500 mg twice daily, or both.

View Article and Find Full Text PDF

A simple HPLC method was developed and validated for the determination of uric acid (UA), xanthine (X) and hypoxanthine (HX) concentrations in human serum to support pharmacodynamic (PD) studies of a novel xanthine oxidase inhibitor during its clinical development. Serum proteins were removed by ultrafiltration. The hydrophilic analytes and the I.

View Article and Find Full Text PDF

To assess the effect of hepatic impairment on the pharmacokinetics, pharmacodynamics, and safety of febuxostat at steady state, multiple once-daily 80-mg oral doses of febuxostat were administered to subjects with normal hepatic function and to subjects with mild or moderate hepatic impairment. There were no statistically significant differences in the plasma pharmacokinetic parameters for unbound febuxostat and its active metabolites between subjects with mild or moderate hepatic impairment and those with normal hepatic function. The percentage decrease in serum uric acid appeared to be lower in hepatic impairment groups (49% [mild] and 48% [moderate]) as compared to the normal hepatic group (62%).

View Article and Find Full Text PDF

To assess the safety, pharmacokinetics, and pharmacodynamics of febuxostat in subjects with normal renal function or renal impairment, febuxostat (80 mg/d) was orally administered for 7 days to subjects with normal renal function (n = 11, CLcr >80 mL/min/1.73 m) or to subjects with mild (n = 6, CLcr 50-80 mL/min/1.73 m), moderate (n = 7, CLcr 30-49 mL/min/1.

View Article and Find Full Text PDF