A Phase 1, Open Label Study To Evaluate The Drug Interaction Potential With Ketoconazole and The Effect Of Food On The Plasma Pharmacokinetics Of The Smoothened Inhibitor PF-04449913

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3857-3857
Author(s):  
M.Naveed Shaik ◽  
Robert R LaBadie ◽  
Dan Rudin ◽  
Wendy J. Levin
Keyword(s):  
Geometric Mean ◽  
Random Effect ◽  
Geometric Mean Ratio ◽  
Open Label ◽  
Post Dose ◽  
Fed State ◽  
Fasted State ◽  
Effect Of Food ◽  
Plasma Pharmacokinetics ◽  
Anti Fungal

Abstract Introduction PF-04449913 is a potent and selective inhibitor of the Hedgehog signaling pathway through binding to the target, Smoothened (SMO). PF-04449913 inhibits Hedgehog (Hh) signaling ex vivo and has demonstrated anti-tumor activity in vivo. PF-04449913 is currently under clinical evaluation in the AML and high risk MDS patient populations, who receive anti-fungal agents routinely as prophylaxis. The preferred anti-fungal agents are azoles which are known strong CYP3A4 inhibitors. Preliminary assessment using individual recombinant P450 enzymes suggests that CYP3A4 plays a major role in mediating the metabolism of PF-04449913. Preliminary results show that PF-04449913 does not inhibit CYPs .Thus, one of the goals of this study was to understand the potential drug-drug interaction (DDI) impact of a strong CYP3A4 inhibitor (ketoconazole) on PF-04449913 plasma exposure to provide dosing guidance. An additional objective was to estimate the effect of a high fat, high calorie meal on single dose PF-04449913 plasma pharmacokinetics (PK). Methods This was an open label, 2-sequence, 3-period, 3-treatment arm, single dose, crossover study in healthy volunteers. Subjects were randomized to receive single doses of 200 mg PF-04449913 in either the fasted or fed state during Periods 1 or 2 with a washout period of at least 8 days between treatments. Subsequently, in Period 3, all subjects received a fixed regimen of ketoconazole (400 mg/day) from Days 1 to 7 and a co-administered single 200 mg PF-04449913 dose on Day 4. Serial blood sampling to determine plasma concentrations of PF-04449913 was performed to 120 hours post dose in Periods 1 and 2, and to 144 hours post dose in Period 3. PF-04449913 in the fasted state was the Reference treatment for both comparisons, while PF-04449913 in the fed state and PF-04449913 + ketoconazole were the Test treatments. Natural log transformed AUCinf (area under the plasma concentration versus time curve from time zero to infinity) and Cmax (maximum observed plasma concentration) for PF-04449913 were analyzed using a mixed effects model with sequence, period and treatment as fixed effects and subject within sequence as a random effect for the effect of food. For the DDI, natural log transformed AUCinf and Cmax for PF-04449913 were analyzed using a mixed effects model with treatment as a fixed effect and subject as a random effect. The adjusted mean differences and 90% confidence intervals (CIs) for the differences from both models were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios. Results PF-04449913 exposure was increased in the presence of ketoconazole, with a geometric mean ratio for AUCinf of 2.40 (90% CI: 2.15 -2.68) and for Cmax of 1.40 (90% CI: 1.24-1.58). For PF-04449913 alone and with ketoconazole, Cmax occurred 1.0 and 2.0 hours after dosing, respectively. The geometric mean ratio for AUCinf for fed state compared to the fasted state was 0.87 (90% CI: 0.78 -0.97) and for Cmax was 0.66 (90% CI: 0.56-0.78). In the fasted and fed state, the PF-0444913 Cmax occurred at 1.0 and 4.0 hours after dosing, respectively. All adverse events (AE) were mild in severity except for one case of moderate AE accelerated idioventricular rhythm in an individual with underlying cardiac issues, which was classified as non-treatment related. Conclusions PF-04449913 plasma exposures and peak concentrations were increased (2.40-fold for AUCinf and 1.40-fold for Cmax) following concurrent administration of ketoconazole in healthy volunteers. These findings provide the upper limit for the PF-04449913 plasma exposures expected with potent metabolic inhibition and define PF-04449913 dosing parameters in AML and high-risk MDS patient trials. While PF-04449913 plasma exposures and peak concentrations were decreased following administration of PF-04449913 in the fed state, the difference in exposures under the fed and fasted conditions was not considered clinically meaningful. Disclosures: Shaik: Pfizer: Employment, Stock Other. LaBadie:Pfizer: Employment, Stock Other. Rudin:Pfizer: Employment. Levin:Pfizer Oncology Business Unit: Employment.

Pharmacokinetics of fixed-dose combination of tenofovir disoproxil fumarate, lamivudine, and efavirenz: results of a randomized, crossover, bioequivalence study

2016 ◽  
Vol 28 (5) ◽  
pp. 491-498 ◽  
Author(s):  
Dhiraj Abhyankar ◽  
Ashish Shedage ◽  
Milind Gole ◽  
Preeti Raut
Keyword(s):  
Tenofovir Disoproxil Fumarate ◽  
Geometric Mean ◽  
Bioequivalence Study ◽  
Fixed Dose Combination ◽  
Fixed Dose ◽  
Geometric Mean Ratio ◽  
Open Label ◽  
Post Dose ◽  
Dose Combination ◽  
The Individual

The objective of this study was to assess the bioequivalence between a fixed-dose combination of tenofovir disoproxil fumarate/lamivudine/efavirenz 300/300/600 mg and the individual innovator products. A randomized, balanced, open-label, two-sequence, two-treatment, two-period, single dose, crossover study in 48 healthy adults was conducted. Dosing was separated by a washout period of 32 days. Twenty-seven blood samples were collected in each period from pre-dose to 72 h post-dose. The data of 45 subjects were analyzed for pharmacokinetics and safety. Ninety percent CIs of geometric mean ratio on Cmax, AUC0–t, and AUC0-inf for tenofovir and lamivudine and on Cmax and AUC0-72 for efavirenz were within the acceptance criteria (80–125%). For tenofovir disoproxil fumarate, the Tmax, Kel, and t1/2 values for the test and reference products were 1.02 versus 0.91 h, 0.04 versus 0.04/h, 18.67 versus 18.46 h, respectively. For lamivudine, the Tmax, Kel, and t1/2 values were: 1.38 versus 1.30 h, 0.21 versus 0.19/h, 3.44 versus 3.91 h, respectively. For efavirenz, the Tmax values for the test and reference products were 3.71 and 3.65 h, respectively. Both the treatments were well tolerated. Our findings suggest that the tested formulation is bioequivalent to the innovators’ formulations, and both treatments were well tolerated.

scholarly journals Pharmacokinetics of Temsavir, the Active Moiety of the Prodrug Fostemsavir, in Subjects with Hepatic Impairment

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S430-S430 ◽  
Author(s):  
Heather Sevinsky ◽  
Mindy Magee ◽  
Peter Ackerman ◽  
Robert Adamczyk ◽  
Jennifer Karkas ◽  
...  
Keyword(s):  
Hepatic Impairment ◽  
Geometric Mean ◽  
Hepatic Function ◽  
Open Label ◽  
Post Dose ◽  
Viral Attachment ◽  
Linear Mixed Effects ◽  
Active Moiety ◽  
Impaired Hepatic Function ◽  
Hiv 1

Abstract Background Fostemsavir (FTR) is a prodrug of temsavir (TMR), a first-in-class attachment inhibitor that binds directly to HIV-1 gp120, preventing initial viral attachment and entry into host CD4+ T cells. TMR is primarily metabolized via hydrolytic and oxidative pathways; impaired hepatic function may alter TMR pharmacokinetics (PK). Methods AI438053 (NCT02467335) was an open-label, nonrandomized study in healthy subjects (HS) and subjects with hepatic impairment (HI), defined by Child-Pugh (CP) score: mild (CPA), moderate (CPB), or severe (CPC). HS were matched for age, body weight, and sex. Subjects received a single oral dose of FTR 600 mg fasted and serial PK samples for TMR were collected up to 96 hours post-dose. Unbound TMR at 1 and 3 hours post-dose was determined. Total and unbound PK parameters were derived by noncompartmental methods. Geometric mean ratios (GMR) and 90% confidence intervals (CI) for HI vs.. HS were derived using linear mixed-effects models. Subjects were monitored for adverse events (AEs). Results 18 subjects with HI (N = 6/CP group) and 12 HS received FTR and completed the study. Total and unbound TMR exposures increased with increasing HI severity (see Table). Total and unbound TMR CLT/F decreased with increasing HI severity. Mean % protein binding of TMR was 81.0% in HS and 79.9%, 81.9%, and 76.5% in CPA, CPB, and CPC HI, respectively, and was independent of TMR concentration. There were no deaths, serious AEs, or discontinuations during the treatment period. Conclusion TMR exposures increase with increasing severity of HI. The increase in TMR exposures in patients with mild or moderate HI is not expected to alter the safety profile of FTR. The risk/benefit of higher TMR exposures in severe HI is under evaluation. Disclosures H. Sevinsky, ViiV Healthcare: Employee, Salary; M. Magee, GlaxoSmithKline: Employee and Shareholder, Salary; P. Ackerman, ViiV Healthcare/GSK: Employee and Shareholder, Salary and Stock; R. Adamczyk, Bristol-Myers Squibb: Employee, Salary; J. Karkas, Bristol Myers Squibb: Employee and Shareholder, Salary; S. Lubin, Bristol-Myers Squibb: Employee, Salary; P. Ravindran, Bristol-Myers Squibb: Employee, Salary; C. Llamoso, ViiV Healthcare: Employee, Salary; T. Eley, Bristol-Myers Squibb: Former Employee during study conduct, Salary; K. Moore, ViiV Healthcare: Employee, Salary

Effect of food on the pharmacokinetics of dronabinol oral solution versus dronabinol capsules in healthy volunteers.

2016 ◽  
Vol 34 (26_suppl) ◽  
pp. 199-199
Author(s):  
Christina Cognata Smith ◽  
D. Alexander Oh ◽  
Neha Parikh ◽  
Varun Khurana ◽  
Santosh Vetticaden
Keyword(s):  
Healthy Volunteers ◽  
Therapeutic Benefit ◽  
Oral Solution ◽  
Individual Variability ◽  
Pharmacokinetic Data ◽  
Inadequate Response ◽  
Open Label ◽  
Post Dose ◽  
Solution Versus ◽  
Fed State

199 Background: Dronabinol, a pharmaceutical tetrahydrocannabinol (THC), capsule is approved for anorexia associated with weight loss in patients with AIDS and for cancer chemotherapy-induced nausea/vomiting in patients with inadequate response to conventional antiemetic therapy. Food effects on absorption and bioavailability of a new dronabinol oral solution was compared with marketed capsules. Methods: In an open-label, single-dose, 3-period crossover study, healthy volunteers were randomized to receive dronabinol oral solution 4.25 mg (fed) or dronabinol capsule 5 mg (fed or fasted), after a 7-day washout period. Doses were administered under a fasted (overnight) or fed state (high-fat/calorie meal 30 minutes pre-dose). Plasma pharmacokinetics was evaluated for dronabinol and the major metabolite, 11-OH-Δ9-THC. Results: Pharmacokinetic data of 54 volunteers were analyzed. In the fed state, initial dronabinol absorption was rapid with oral solution versus capsules (mean Tlag, 0.15 vs 2.02 h), and 100% and 15% of volunteers receiving oral solution and capsules, respectively, had detectable plasma dronabinol levels 30 minutes post-dose. Inter-individual variability in plasma dronabinol concentrations during early absorption was less with oral dronabinol solution (%CV: 82.79%, 83.94%, and 90.68%) versus capsules (%CV: 318.54%, 250.33%, and 182.01%) observed at 0.5, 1, and 2 h, respectively, after dosing. Food increased mean AUC0-t similarly for dronabinol oral solution and capsules, versus capsules with fasting, increasing exposure to oral solution and capsules 2.1- to 2.4-fold. Mean Tmax was similarly delayed for dronabinol oral solution (7.7 h) and capsules (5.6 h) with food relative to fasting (1.7 h). On the basis of 11-OH-Δ9-THC plasma levels, AUC0-t up to 48 h postdose and AUC0-inf were found to be similar for the oral solution and capsules under fed conditions. Conclusions: An appreciable food effect was observed for dronabinol oral solution and capsules. Dronabinol oral solution may offer therapeutic benefit to patients given its rapid absorption and lower inter-individual variability compared with dronabinol capsules. Clinical trial information: NCT01448772.

Single-Dose Pharmacokinetics of Indinavir and the Effect of Food

1998 ◽  
Vol 42 (2) ◽  
pp. 332-338 ◽  
Author(s):  
Kuang C. Yeh ◽  
Paul J. Deutsch ◽  
Heidi Haddix ◽  
Michael Hesney ◽  
Vicki Hoagland ◽  
...  
Keyword(s):  
Single Dose ◽  
Renal Clearance ◽  
Dose Range ◽  
Systemic Circulation ◽  
Tubular Secretion ◽  
Fed State ◽  
Fasted State ◽  
Indinavir Sulfate ◽  
Effect Of Food ◽  
Intrinsic Solubility

ABSTRACT Indinavir sulfate is a human immunodeficiency virus type 1 (HIV-1) protease inhibitor indicated for treatment of HIV infection and AIDS in adults. The purpose of this report is to summarize single-dose studies which characterized the pharmacokinetics of the drug and the effect of food in healthy volunteers. Indinavir concentrations in plasma and urine were obtained by high-pressure liquid chromatography and UV detection assay methods. The results indicate that indinavir was rapidly absorbed in the fasting state, with the time to the maximum concentration in plasma occurring at ∼0.8 h for all doses studied. Over the 40- to 1,000-mg dose range studied, concentrations in plasma and urinary excretion of unchanged drug increased greater than dose proportionally. The nonlinear pharmacokinetics were attributed to the dose-dependent oxidative metabolism of first-pass metabolism as well as to metabolism in the systemic circulation. Renal clearance slightly exceeded the glomerular filtration rate, suggesting a net tubular secretion component. At high concentrations in plasma, tubular secretion appeared to be lowered because there was a trend for a decreased renal clearance. Administration of 400 mg of indinavir sulfate following a high-fat breakfast resulted in a blunted and decreased absorption (areas under the concentration-time curves [AUCs], 6.86 μM·h in the fasted state versus 1.54 μM·h in the fed state; n = 10). However, two types of low-fat meals were found to have no significant effect on the absorption of 800 mg of indinavir sulfate (AUCs, 23.15 μM·h in the fasted state versus 22.71 and 21.36 μM·h, respectively, in the fed state; n = 11). Immediately following dosing, the concentrations of indinavir in urine often exceeded its intrinsic solubility. To reduce the risk of nephrolithiasis, it is recommended that indinavir sulfate be administered with water.

scholarly journals Population Pharmacokinetic Modelling and Simulation to Determine the Optimal Dose of Nanoparticulated Sorafenib to the Reference Sorafenib

Pharmaceutics ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 629
Author(s):  
Ki Young Huh ◽  
Sejung Hwang ◽  
Sang Yeob Park ◽  
Hye Jung Lim ◽  
Miryung Jin ◽  
...  
Keyword(s):  
Compartmental Analysis ◽  
Optimal Dose ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
Open Label ◽  
Post Dose ◽  
Multikinase Inhibitor ◽  
Final Model ◽  
Fasted State ◽  
Second Period

Sorafenib, an oral multikinase inhibitor, exhibits a highly variable absorption profile due to enterohepatic reabsorption and poor solubility. SYO-1644 improved the solubility of sorafenib by nanoparticulation technology leading to enhanced bioavailability. To evaluate the pharmacokinetically equivalent dose of SYO-1644 to the reference Nexavar® 200 mg, a randomized, open-label, replicated two-period study was conducted in healthy volunteers. A total of 32 subjects orally received a single dose of the following assigned treatment under a fasted state in the first period and repeated once more in the second period with a two-week washout: SYO-1644 100, 150 and 200 mg and Nexavar® 200 mg. Pharmacokinetic (PK) samples were collected up to 168 h post-dose. The PK profile was evaluated by both non-compartmental analysis and population PK method. With the final model, 2 × 2 crossover trial scenarios with Nexavar® 200 mg and each dose of SYO-1644 ranging from 100 to 150 mg were repeated 500 times by Monte Carlo simulation, and the proportion of bioequivalence achievement was assessed. Transit absorption compartments, followed by a one-compartment model with first-order elimination and enterohepatic reabsorption components were selected as the final model. The simulation results demonstrated that the SYO-1644 dose between 120 and 125 mg could yielded the highest proportion of bioequivalence.

scholarly journals CTNI-09. A PHASE I HEALTHY VOLUNTEER STUDY ON THE RELATIVE BIOAVAILABILITY AND FOOD EFFECT OF CAPSULE AND GRANULE FORMULATIONS OF SELUMETINIB

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii43-ii43
Author(s):  
Sarit Cohen-Rabbie ◽  
Alexandra Mattinson ◽  
Karen So ◽  
Nan Wang ◽  
Eileen McBride ◽  
...  
Keyword(s):  
Phase I ◽  
Pediatric Patients ◽  
Food Effect ◽  
Geometric Mean ◽  
Open Label ◽  
Capsule Formulation ◽  
Dry Eyes ◽  
Fasted State ◽  
Volunteer Study ◽  
Granule Formulation

Abstract Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly selective allosteric MEK 1/2 inhibitor approved by the FDA as a capsule formulation for treatment of pediatric patients ≥ 2 years old with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas. A new granule formulation is being developed to support dose flexibility and for patients unable to swallow capsules. This Phase I, open-label, single-center, randomized crossover pharmacokinetics study (NCT03649165) investigated the new granule versus capsule formulation in both fasted and fed (low-fat) states. Twenty-four healthy adult male volunteers were randomized to receive single-dose selumetinib in one of four treatment sequences: 25 mg granule (fasted); 50 mg capsule (fasted); 25 mg granule (fed); and 50 mg capsule (fed). Primary endpoint: to compare pharmacokinetics of the formulations in fasted state. Secondary endpoints: pharmacokinetics of the formulations in fasted versus fed states, granule palatability, safety and tolerability. In fasted state, a slight delay in absorption of selumetinib by ~0.60 h, with geometric mean ratios (90% CI) of 0.65 (0.58, 0.74) for Cmax/dose and 0.87 (0.81, 0.92) for AUC/dose, was detected when administered as granule versus capsule. For granule in fed versus fasted states, geometric mean Cmax and AUC ratios (90% CI) were 0.61 (0.51, 0.72) and 0.97 (0.91, 1.02). For capsule in fed versus fasted states, geometric mean Cmax and AUC ratios (90% CI) were 0.40 (0.33, 0.48) and 0.62 (0.55, 0.70). Granule palatability was acceptable; volunteers indicated they would take it again. Selumetinib was well-tolerated; for both formulations, few adverse events of mild intensity were reported; dry eyes (fasted) versus dry eyes and rhinorrhea (fed) were most frequent. This was the first study to test the granule formulation in humans; results indicate the granule formulation has similar AUC to the capsule formulation and minimal food effect, supporting planned clinical trials in pediatric patients.

scholarly journals Pharmacokinetics and Bioequivalence of Two Formulations of Eldecalcitol Capsules in healthy Chinese volunteers under fasting and fed conditions and effects of food on pharmacokinetic profiles

2021 ◽  
Author(s):  
Juan Wu ◽  
Yu-ru Fan ◽  
Liang Zheng ◽  
Yue-yue Liu ◽  
Qian Zhang ◽  
...  
Keyword(s):  
Adverse Events ◽  
Crossover Study ◽  
Oral Absorption ◽  
Open Label ◽  
Post Dose ◽  
Effect Of Food ◽  
Healthy Chinese ◽  
Scheduled Time ◽  
T Values ◽  
Extent Of Absorption

Aims： The objective of this study was to evaluate the bioequivalence of two formulations of eldecalcitol (0.75 μg ) under fasting and fed conditions, and to explore the effect of food on the pharmacokinetic (PK) properties of eldecalcitol in healthy Chinese volunteers. Methods： A single-center, open-label, randomized, three-period, three-sequence, crossover study was performed in 27 healthy Chinese volunteers under fasting conditions. Meanwhile, a two-way crossover study was performed in 28 healthy volunteers under fed conditions. Blood samples were collected at scheduled time spots from 0 hour pre dose to 168 hours post dose following administration of 0.75 μg eldecalcitol. The PK parameters for bioequivalence evaluation calculated by non-compartment analysis include Cmax, AUC and AUC. Monitoring of adverse events throughout the study. Results： The 90% confidence intervals of the test/reference AUC ratio and C ratio were within the acceptance criteria. Under the fasting condition, T values were 3.987 h and 3.489 h in subjects after given the test and reference formulation respectively. While in the fed study, the Tmax were 9.006 h and 6.007 h respectively. Therefore, the Tmax was significantly increased (P < 0.05) under fed conditions. No severe adverse events occurred during the study and all adverse events were mild and transient. Conclusion: The generic product of eldecalcitol was bioequivalent to the reference product in terms of the rate and extent of absorption under both fasting and fed conditions. Food intake prolongs the oral absorption of eldecalcitol but does not significantly influence the system exposure.

scholarly journals A Randomized Phase 1 Pharmacokinetic Study Comparing the Potential Biosimilar LRG201902 With Liraglutide (Victoza®) in Healthy Male Subjects

2021 ◽  
Vol 11 ◽  
Author(s):  
Gang Mai ◽  
Lianlian Fan ◽  
Mupeng Li ◽  
Peiwen Zhang ◽  
Chunyan Gan ◽  
...  
Keyword(s):  
Phase 1 ◽  
Geometric Mean ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Post Dose ◽  
Time Profiles ◽  
Healthy Adult Male ◽  
To Receive ◽  
Second Period ◽  
Male Subjects

Objective: Pharmacokinetic (PK) similarity between biosimilar candidate LRG201902 and European Union-sourced liraglutide reference product (Victoza®) was evaluated. Safety and immunogenicity were also assessed.Methods: This single-dose, randomized, open-label, 2-period crossover study (CTR20192342) was conducted in thirty-eight healthy adult male subjects. Volunteers were randomized 1:1 at the beginning to receive a single 0.6 mg dose of Victoza® or LRG201902 by subcutaneous injection during the first period. Following 8 days washout period, all subjects received the alternate formulation during the second period. Blood samples were collected up to 72 h after administration. The primary pharmacokinetic endpoints were AUC0–t, AUC0–∞, and Cmax. Pharmacokinetic similarity was achieved if 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) of AUC0-t, AUC0–∞, and Cmax were within the range of 80–125%. Other pharmacokinetic parameters including Tmax, t½, and λz were also measured. Safety profile and immunogenicity data were collected from each subject.Results: Cmax, AUC0–t, and AUC0–∞ were similar between the two groups. GMRs of Cmax, AUC0–t, and AUC0–∞ were 113.50%, 107.21%, and 106.97% between LRG201902 and Victoza® respectively. The 90% CIs for the GMRs of Cmax, AUC0-t, and AUC0–∞ were all within the PK equivalence criteria. Mean serum concentration-time profiles, secondary pharmacokinetic parameters (Tmax, t½, and λz) were comparable between groups. Treatment-related adverse events were reported by 27.8% and 23.7% subjects in the LRG201902 and Victoza® arms, respectively. All post-dose samples were detected negative for anti-drug antibodies.Conclusion: This study demonstrates pharmacokinetic similarity of LRG201902 to Victoza® in healthy subjects. The safety and immunogenicity profiles were similar for the two products.

Phase I pharmacokinetic(PK)/food effect and safety study of satraplatin in patients (pts) with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12014-12014
Author(s):  
B. J. George ◽  
A. D. Ricart ◽  
E. Calvo ◽  
Q. Chu ◽  
J. Sarantopoulos ◽  
...  
Keyword(s):  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Phase Iii ◽  
Fed State ◽  
Fasted State ◽  
Heavily Pretreated ◽  
Effect Of Food ◽  
Hormone Refractory ◽  
Grade 3 ◽  
Tumor Types

12014 Background: Satraplatin (S) is a novel oral platinum analog that has demonstrated preliminary activity in hormone refractory prostate cancer (HRPC). A large (950 pts) worldwide, randomized phase III trial evaluating S as 2nd line therapy for HRPC recently completed enrollment. The current study was designed to determine the PKs of S under fasted and fed conditions, as well as treatment efficacy and toxicity. Methods: S was administered orally at 80 mg/m2/day (d) on d1–5 q 35 days, with prophylactic antiemetics. For the 1st cycle, pts were randomized to receive d1 and d5 doses of S in either the fed or fasted state when PK sampling was performed. The fed/fasted state was reversed for the 2nd cycle. Subsequent doses of S were given in the fasted state. Results: 17 pts were enrolled (9M/8F), median age 62 (range 33–78) and tumor types: HRPC (7), breast (3), 1 each with anal, parotid, leiomyosarcoma, Merkel cell, ovarian, mesothelioma, and neuroendocrine tumor. The median no. of prior regimens was 3 (range 1–8). A total of 58 cycles of S were given. Grade 3–4 hematologic toxicities (1st 2 cycles) included: neutropenia (11%), thrombocytopenia (24%) and anemia (24%). The hematologic nadir occurred during week 4. There was no grade 3–4 nausea, vomiting or diarrhea. No significant cardiac, renal, hepatic, or neurologic toxicity was observed. The peak plasma concentration (Cmax) for platinum in plasma ultrafiltrate (PUF) was decreased by 20% when S was administered following a high fat meal compared to the fasting condition. There was no effect of food on AUC0–24 hr. The time of Cmax (Tmax) was delayed in the fed state. Table shows PK parameters. One PR (HRPC) and 4 SD ≥ 5 months (breast, ovarian, parotid and HRPC) were confirmed. Conclusions: There is an effect of food on the Cmax, however the clinical implications are unknown at this time. For this reason, it is recommended that S be administered to pts in the fasting state. At the dose of 80 mg/m2/day, S was well tolerated in this group of heavily pretreated patients. [Table: see text] [Table: see text]

scholarly journals Comparative Bioavailability of Amphetamine Extended-Release Oral Suspension and Extended-Release Mixed Amphetamine Salts

CNS Spectrums ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 163-163
Author(s):  
Antonio Pardo ◽  
Mohammed Bouhajib ◽  
Eman Rafla ◽  
Thomas R. King ◽  
Judith C. Kando
Keyword(s):  
Single Dose ◽  
Safety Assessment ◽  
Extended Release ◽  
Healthy Adult ◽  
Geometric Mean ◽  
Oral Suspension ◽  
Open Label ◽  
Post Dose ◽  
Comparative Bioavailability ◽  
The Mean

AbstractPurposeThis open-label, single-dose, randomized, two-period, two-treatment, two-sequence, crossover study evaluated the comparative bioavailability between amphetamine extended-release oral suspension (treatment A: AMPH EROS, Dyanavel XR 2.5 mg/mL, 18.8 mg amphetamine base per 7.5 mL) and extended-release mixed amphetamine salts (treatment B: ER MAS, Adderall XR 30 mg capsules, equivalent to 18.8 mg amphetamine base per capsule) after a single dose in healthy adult subjects, under fasted conditions.MethodsThe crossover design allowed for intra-subject PK comparisons. Relative comparable bioavailability was determined by a statistical comparison of the AUC and Cmax parameters for both d- and l-amphetamine, where the geometric mean ratios for AUC and Cmax were within the 90% confidence limits (80.0%–125.0%) to determine comparable bioavailability between test products. Subjects in sequence 1 received treatment A followed by B; subjects in sequence 2 received treatment B followed by treatment A. PK samples were obtained at 0 (pre-dose) through 60 hours post-dose. The safety assessment was based on reported frequency and severity of adverse events.ResultsThirty (30) subjects were enrolled and 28 completed. The mean age of subjects was 35 years, with a mean BMI of 25.9 kg/m2. Most subjects were Male (63.3%) and Black (56.7%). The geometric mean ratios for Cmax and all AUC measurements were within the 80–125% bound indicating comparable bioavailability between both test products. Both test products were generally well-tolerated with no serious AEs reported.ConclusionsThe bioavailability of a single 7.5 mL dose of AMPH EROS 2.5 mg/mL was comparable to a single 30 mg capsule dose of ER MAS. AMPH EROS (both d- and l-amphetamine) showed equivalent peak and overall exposure to ER MAS under fasted conditions.FundingTris Pharma, Inc.

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