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.

A single-dose comparative bioavailability study of dronabinol oral solution versus dronabinol capsules in healthy volunteers.

2016 ◽  
Vol 34 (26_suppl) ◽  
pp. 198-198
Author(s):  
Christina Cognata Smith ◽  
Neha Parikh ◽  
William G. Kramer ◽  
Varun Khurana ◽  
Santosh Vetticaden
Keyword(s):  
Single Dose ◽  
Plasma Concentration ◽  
Healthy Volunteers ◽  
Oral Solution ◽  
Individual Variability ◽  
Pharmacokinetic Data ◽  
Maximum Plasma ◽  
Inadequate Response ◽  
Solution Versus ◽  
Time Zero

198 Background: The capsule formulation of dronabinol, a pharmaceutical tetrahydrocannabinol (THC), is approved for anorexia associated with weight loss in patients with AIDS and for cancer chemotherapy-associated nausea/vomiting in patients with inadequate response to conventional antiemetics. A new oral formulation (i.e., dronabinol solution) was evaluated in a bioequivalence study versus currently marketed dronabinol capsules. Methods: In an open-label, 2-treatment, 2-sequence, 4-period, single-dose crossover study, healthy volunteers were randomized to receive 1 of 2 treatment sequences (T-R-T-R or R-T-R-T; T = dronabinol 4.25 mg oral solution and R = dronabinol 5 mg capsules). Dosing occurred after an overnight fast, with a minimum 7-day washout period between treatment periods. A validated liquid chromatography-tandem mass spectrometry method was used to determine plasma concentrations of dronabinol and the primary metabolite 11-OH-Δ9-THC. Results: Fifty-one of 52 enrollees had pharmacokinetic data for analysis. Mean pharmacokinetics were (oral solution vs capsule): Cmax (2.0 vs 2.4 ng/mL), median Tmax (1.0 vs 1.5 h), AUC0-∞ (3.8 vs 4.1 h∙ng/mL), and t1/2 (5.6 vs 3.1 h). The 2 formulations were bioequivalent with respect to maximum plasma concentration (Cmax; reference-scaled criteria) and area under the plasma concentration-time curve (from time zero to last measurable concentration and from time zero to infinity [AUC0-∞]; average bioequivalence) of dronabinol. The data for the 11-OH-Δ9-THC metabolite provide further support for the bioequivalence of the 2 products. Post hoc analysis demonstrated that all volunteers (100%) had detectable plasma dronabinol concentrations at 15 min with the oral solution compared with < 25% of volunteers for the capsules. Intra-individual variability was lower with oral solution versus capsules (for AUC0-∞, 13.5% vs 36.8%, respectively). Conclusions: Dronabinol oral solution 4.25 mg was bioequivalent to dronabinol capsules 5 mg, and exhibited quicker onset of detectable levels and lower intra-individual variability in comparison with dronabinol capsules 5 mg. Clinical trial information: NCT01448772.

scholarly journals Bioavailability study of dronabinol oral solution versus dronabinol capsules in healthy volunteers

2016 ◽  
Vol Volume 8 ◽  
pp. 155-162
Author(s):  
Neha Parikh ◽  
William Kramer ◽  
Varun Khurana ◽  
Christina Cognata Smith ◽  
Santosh Vetticaden
Keyword(s):  
Healthy Volunteers ◽  
Oral Solution ◽  
Solution Versus ◽  
Bioavailability Study

A single-dose comparative bioavailability study of dronabinol oral solution versus dronabinol capsules in healthy volunteers.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. e21595-e21595
Author(s):  
Neha Parikh ◽  
William G. Kramer ◽  
Varun Khurana ◽  
Christina Cognata Smith ◽  
Santosh Vetticaden
Keyword(s):  
Single Dose ◽  
Healthy Volunteers ◽  
Oral Solution ◽  
Solution Versus ◽  
Bioavailability Study ◽  
Comparative Bioavailability ◽  
Comparative Bioavailability Study

scholarly journals Enhanced Bioavailability of Itraconazole in Hydroxypropylβ-Cyclodextrin Solution versus Capsules in Healthy Volunteers

1998 ◽  
Vol 42 (7) ◽  
pp. 1862-1865 ◽  
Author(s):  
Joseph A. Barone ◽  
Bruce L. Moskovitz ◽  
Joseph Guarnieri ◽  
Alan E. Hassell ◽  
John L. Colaizzi ◽  
...  
Keyword(s):  
Crossover Study ◽  
Healthy Volunteers ◽  
Oral Solution ◽  
Solution Versus ◽  
Male Volunteers ◽  
The Times

ABSTRACT The bioavailabilities and bioequivalences of single 200-mg doses of itraconazole solution and two capsule formulations were evaluated in a crossover study of 30 male volunteers. The two capsule formulations were bioequivalent. The bioavailabilities of the solutions itraconazole and hydroxyitraconazole were 30 to 33% and 35 to 37% greater, respectively, than those of either capsule. However, the maximum concentrations of the drug in plasma (C max), the times to C max, and the terminal half-lives were comparable for all three formulations. These data indicate that the bioavailabilities of itraconazole and hydroxyitraconazole are enhanced when administered as an oral solution instead of capsules.

scholarly journals Bioequivalence of intramuscular and subcutaneous peginterferon beta-1a: results of a phase I, open-label crossover study in healthy volunteers

2021 ◽  
Vol 14 ◽  
pp. 175628642097522
Author(s):  
Yuan Zhao ◽  
Kun Chen ◽  
Nancy Ramia ◽  
Sangeeta Sahu ◽  
Achint Kumar ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Phase I ◽  
Crossover Study ◽  
Healthy Volunteers ◽  
Treatment Option ◽  
Area Under The Curve ◽  
Open Label ◽  
Post Dose ◽  
Maximum Serum ◽  
Alternative Treatment Option

Background: Peginterferon beta-1a administered every 2 weeks via subcutaneous (SC) injection is approved to treat adult patients with relapsing-remitting multiple sclerosis (RRMS) and relapsing forms of multiple sclerosis (RMS). However, associated injection site reactions (ISRs) can lead to treatment discontinuation. Prior studies with interferon beta-1a reported a lower frequency of ISRs with intramuscular (IM) administration than with SC administration. IM administration of peginterferon beta-1a may therefore represent a useful alternative treatment option. Methods: A phase I, open-label, two-period crossover study randomized healthy volunteers to receive a single dose of peginterferon beta-1a 125 mcg administered IM followed by a single 125 mcg dose administered SC after a 28-day washout or vice versa. Blood samples were collected up to 504 h post dose to determine pharmacokinetic (PK) and pharmacodynamic (PD) profiles. The primary endpoint was assessment of bioequivalence based on maximum serum concentration (Cmax) and area under the curve from time zero extrapolated to infinity (AUCinf). Other PK parameters, as well as PD (serum neopterin) and safety profiles, were also evaluated. Results: The study enrolled 136 participants. Bioequivalence of IM and SC peginterferon beta-1a was established for both Cmax ([least squares (LS)] mean IM/SC ratio: 1.083 [90% confidence interval (CI), 0.975–1.203]) and AUCinf (LS mean IM/SC ratio: 1.089 [90% CI, 1.020–1.162]). Other PK and PD parameters were similar between administration routes, although moderate to high inter-subject variability was observed for IM and SC. Safety profiles were generally balanced between IM and SC administration. ISRs occurred at a lower frequency with IM [14.4% (95% CI, 8.89–21.56%)] than with SC [32.1% (95% CI, 24.29–40.70%)] administration ( p = 0.0005). Conclusions: These results demonstrate bioequivalence between peginterferon beta-1a IM and SC and support the consideration of IM injection of peginterferon beta-1a as a viable treatment option in patients with RRMS and RMS.

scholarly journals Pharmacokinetics of a Novel Form of Biotin, Magnesium Biotinate, in Healthy Subjects (P06-027-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Sara Perez Ojalvo ◽  
Sarah Sylla ◽  
James Komorowski
Keyword(s):  
Clinical Study ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Blood Levels ◽  
Pharmacokinetic Data ◽  
Open Label ◽  
Post Dose ◽  
Funding Sources ◽  
Study Results

Abstract Objectives Biotin, also known as vitamin B7, plays an important role in the metabolization of nutrients into energy. Magnesium biotinate (MgB) is a novel biotin compound that has been shown to be 40 times more soluble than D-Biotin. Preclinical evidence has shown that MgB is well absorbed into the bloodstream and tissues, particularly the brain, over time. The following pharmacokinetic study was carried out to further explore the absorption and bioavailability of MgB. Methods In an open-label clinical study, 30 healthy female subjects (18–45 years, BMI 18.0–29.9 kg/m2) were randomized to receive a single oral capsule containing one of the following doses of MgB (n = 10 per group): 1) 10 mg MgB, 2) 40 mg MgB, 3) 100 mg MgB. Serial blood samples were collected in K2-EDTA tubes at pre-dose (within 1 hour of dose) and at 0.5, 1.0, 1.5, 3.0 and 6.0 hours post-dose. Plasma samples were analyzed for biotin by LC/MS/MS. Pharmacokinetic data were calculated for each dose group. Results Study results showed that plasma biotin levels increased at 0.5, 1.0, 1.5, 3.0 and 6.0 hours post-dose for all groups. However, the largest biotin increase was seen in the 100 mg group (Figure 1). Peak plasma concentrations were observed as follows: 84.8 ng/mL 1 hour after a 10 mg dose, 214.6 ng/mL 1.5 hours after a 40 mg dose, and 508.5 ng/mL 1.5 hours after a 100 mg dose. Area under the curve values increased with increasing biotin dose level (10 mg: 210.0 ng*h/mL; 40 mg: 605.1 ng*h/mL; 100 mg: 1652.4 ng*h/mL). No adverse effects were observed. Conclusions Results from this single-dose pharmacokinetic clinical study demonstrate that magnesium biotinate is a bioavailable form of biotin, with increasing blood levels associated with increasing dose levels. Funding Sources This study was funded by JDS Therapeutics, LLC. Supporting Tables, Images and/or Graphs

scholarly journals Pharmacokinetics of chloroquine and primaquine in healthy volunteers

2022 ◽  
Vol 21 (1) ◽  
Author(s):  
André Daher ◽  
Douglas Pereira Pinto ◽  
Laís Bastos da Fonseca ◽  
Heliana Martins Pereira ◽  
Diego Medeiros Dias da Silva ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Treatment Efficacy ◽  
Analytical Methods ◽  
Vivax Malaria ◽  
Plasma Concentrations ◽  
Open Data ◽  
Blood Levels ◽  
Pharmacokinetic Data ◽  
Open Label ◽  
Serious Adverse Events

Abstract Background Vivax malaria is a neglected disease. There is an irrefutable need for better treatments with higher acceptability and efficacy. The treatment efficacy is influenced by many factors, including bioavailability. Hence, a straightforward strategy to improve vivax malaria treatment efficacy is the deployment of good quality formulations of primaquine and chloroquine. As these treatments were developed more than 70 years ago, many of the available data on blood levels of both drugs are based on obsolete analytical methodologies or pharmaceutical formulations, which are not available anymore. Herein, the results of three bioequivalence studies are presented, providing individual pharmacokinetic data on chloroquine and primaquine of more than a hundred healthy volunteers and using up-to-date analytical methods. Methods Three trials were designed as a single centre, randomized, single dose, open label, fasting, crossover bioequivalence studies comparing a new coated chloroquine tablet to the uncoated tablet, and 5 and 15 mg primaquine formulations to either an international reference product or the currently distributed tablets. Plasma concentrations of chloroquine and primaquine were measured using a validated HPLC–MS/MS method in accordance with current international regulatory requirements for bio-analytical methods. Results In total, a hundred eleven healthy volunteers of both genders were included in the three studies (n = 32; 30 and 56 respectively). No serious adverse events occurred. Drugs levels were measured in 5,520 blood samples. The estimated ratio of the geometric means of Cmax, AUC0-t and AUC0-inf of test and reference drugs and their 90% CI for chloroquine 150 mg, primaquine 15 mg and primaquine 5 mg were: 95.33% (89.18; 101.90), 86. 85% (82.61; 91.31), and 84.45% (76.95; 92.67); 93.28% (81.76; 106.41), 94.52% (86.13; 103.73) and 93.93% (85.83; 102.79); 97.44% (90.60; 104.78), 93.70% (87.04; 100.87) and 91.36% (85.27; 97.89), respectively. As Cmax and AUC0-t 90% CI were within the acceptance interval of 80–125% in all cases, the formulations tested were bioequivalent. Conclusions In conclusion, the three studies provided detailed chloroquine and primaquine pharmacokinetic data in accordance with current regulatory standards. Together with other open data initiatives, this individual data may increase the accuracy of pharmacokinetic models guiding best dose, new combinations, regimens and formulations to optimize the current chloroquine and primaquine treatments for vivax malaria. The data presented here may support the deployment of high-quality drugs and evidence-based public health policies.

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

2017 ◽  
Vol Volume 9 ◽  
pp. 9-17 ◽  
Author(s):  
D. Alexander Oh ◽  
Neha Parikh ◽  
Varun Khurana ◽  
Christina Cognata Smith ◽  
Santosh Vetticaden
Keyword(s):  
Healthy Volunteers ◽  
Oral Solution ◽  
Solution Versus ◽  
Effect Of Food

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, pharmacodynamics, and tolerability of BCD-017, a novel pegylated filgrastim: Results of open-label controlled phase I study with dose escalation in healthy volunteers.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 9060-9060
Author(s):  
Kirill D. Nikitin ◽  
Sergei B. Fitilev ◽  
Tatiana V. Chernovskaya ◽  
Elena G. Rudenko ◽  
Alexander V. Vozzhaev ◽  
...  
Keyword(s):  
Phase I ◽  
Healthy Volunteers ◽  
Phase I Study ◽  
Phase Ii Study ◽  
Open Label ◽  
Post Dose ◽  
Median Increase ◽  
Open Label Phase ◽  
To Receive ◽  
Median Maximum

9060 Background: Pegfilgrastim (conjugate of filgrastim and 20 kDa PEG) is approved for treatment of chemotherapy-associated neutropenia. BCD-017 is a covalent conjugate of filgrastim with 30 kDa PEG. Increased molecular weight of PEG molecule may provide additional benefits compared to pegfilgrastim. We have conducted this open-label phase I study to assess the PK, PD and tolerability of BCD-017. Methods: 24 healthy male volunteers signed the informed consent and were sequentially assigned to receive 1, 3 or 9 mg of BCD-017 or 5 mcg/kg/day of filgrastim for 7 days, 6 volunteers per group. Outcome measures included absolute neutrophil count (ANC) and СD34+ cell count, PK parameters and adverse events (AEs). Results: BCD-017 induced a fast and significant increase of ANC. Median maximum ANC (ANCmax) for BCD-017 1, 3, 9 mg and filgrastim was 18.68 (10.62-21.02), 25.92 (15.43-28.07), 32.22 (18.22-45.79), and 28.21 (21-31.95) ×103 cells/mm3, respectively; median time to ANCmax was 24 (12-24); 48 (24-72); 72 (48-72); and 132,5 (12-169) h, respectively; median increase in СD34+ cells number 96 h post dose was 4.7 (1.2-6.5), 6.5 (1.7-12.3), 40.9 (24.5-102), and 17.8 (3.3-35.2) times, respectively. Filgrastim serum concentration was analyzed using ELISA. Median Cmax for BCD-017 3 and 9 mg and filgrastim was 45 (31-65), 446 (191-649), and 40 (20-54) ng/mL, respectively; median Tmax was 48 (24-72), 36 (24-48), and 8 (6-8) h respectively; median T1/2 was 65 (51-70), 46 (41-57), and 6.7 (6.2-7.6) h, respectively. BCD-017 was well tolerated. No dose-limiting AEs were observed. AEs included headache, back pain, myalgia, arthralgia, thrombocytopenia, hyperuricemia, alkaline phosphatase/LDH increased. All AEs were of grade 1-2. Compared to filgrastim, the best tolerability was observed in 3 mg group. Conclusions: BCD-017 is shown to be a potent stimulator of granulopoiesis. BCD-017 3 mg did not differ from filgrastim in terms of ANC increase and its safety was shown in healthy volunteers. Further phase II study of BCD-017 for treatment and prophylaxis of neutropenia in patients receiving cytotoxic chemotherapy is necessary.

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