Clinically Significant Pharmacokinetic Interaction between Colchicine and Ritonavir in Healthy Volunteers

2013 ◽  
Vol 5 ◽  
pp. CMT.S10561 ◽  
Author(s):  
Suman Wason ◽  
Jennifer L. DiGiacinto ◽  
Matthew W. Davis
Keyword(s):  
Healthy Volunteers ◽  
Multiple Dose ◽  
Plasma Concentrations ◽  
Pharmacokinetic Interaction ◽  
Concomitant Administration ◽  
Study Data ◽  
Open Label ◽  
Time Curve ◽  
Clinically Significant ◽  
Cyp3a4 Enzyme

Colchicine is a substrate for cytochrome 3A4 (CYP3A4) enzyme and P-glycoprotein efflux transporter (P-gp); consequently, concomitant administration with drugs that inhibit these have the potential to cause clinically significant increases in colchicine plasma concentrations and precipitate adverse events. Ritonavir, a protease inhibitor, elicits potent CYP3A4 and P-gp inhibitory activity. In this open-label, nonrandomized, one-sequence, two-period study, 24 healthy volunteers received a single 0.6-mg dose of colchicine alone and together with multiple-dose ritonavir (100 mg twice daily for 4 days) to evaluate drug-drug interactions. Serial blood samples were collected for the determination of colchicine plasma concentrations. Standard pharmacokinetic parameter values were calculated along with 90% confidence intervals (ie, area under the concentration-time curve plasma from time zero to the time of last quantifiable concentration [AUC0-t and AUC0-∞], maximum drug concentration [Cmax]) for colchicine alone and colchicine combined with multiple-dose ritonavir. The mean Cmax and AUC0-t were significantly increased (170% and 245%, respectively) when colchicine was coadministered with ritonavir as compared with colchicine alone. Study data confirm the need for a dose adjustment (approximately 50% reduction) when colchicine is coadministered with strong CYP3A/P-gp inhibitors.

scholarly journals Effects of Danshen Ethanol Extract on the Pharmacokinetics of Fexofenadine in Healthy Volunteers

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
Furong Qiu ◽  
Jin Zeng ◽  
Songcan Liu ◽  
Min He ◽  
Leilei Zhu ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Interaction Design ◽  
Plasma Concentrations ◽  
Ethanol Extract ◽  
Pharmacokinetic Interaction ◽  
Tanshinone Iia ◽  
Oral Clearance ◽  
Open Label ◽  
The Mean

This study investigated the effect of multidose administration of danshen ethanol extract on fexofenadine pharmacokinetics in healthy volunteers. A sequential, open-label, two-period pharmacokinetic interaction design was used. 12 healthy male volunteers received a single oral dose of fexofenadine (60 mg) followed by danshen ethanol extract (1 g orally, three times a day) for 10 days, after which they received 1 g of the danshen extract with fexofenadine (60 mg) on the last day. The plasma concentrations of fexofenadine was measured by LC-MS/MS. After 10 days of the danshen extract administration, the mean AUC andCmax⁡of the fexofenadine was decreased by 37.2% and 27.4% compared with the control, respectively. The mean clearance of fexofenadine was increased by 104.9%. Thein vitrostudy showed that tanshinone IIA and cryptotanshinone could induce MDR1 mRNA. This study showed that multidose administration of danshen ethanol extract could increase oral clearance of fexofenadine. The increased oral clearance of fexofenadine is attributable to induction of intestinal P-glycoprotein.

Effect of Terbinafine on Theophylline Pharmacokinetics in Healthy Volunteers

1998 ◽  
Vol 42 (3) ◽  
pp. 695-697 ◽  
Author(s):  
Eric F. Trépanier ◽  
Anne N. Nafziger ◽  
Guy W. Amsden
Keyword(s):  
Healthy Volunteers ◽  
Multiple Dose ◽  
Treatment Phase ◽  
Pharmacokinetic Parameters ◽  
Noncompartmental Analysis ◽  
Open Label ◽  
Time Curve ◽  
Blood Samples ◽  
Concentration Time ◽  
Randomized Crossover Study

ABSTRACT Twelve healthy volunteers were enrolled in an open-label, randomized, crossover study. Subjects received single doses of theophylline (5 mg/kg) with and without multiple-dose terbinafine, and 11 blood samples were collected over 24 h. The study phases were separated by a 4-week washout period. Theophylline serum data were modeled via noncompartmental analysis. When the control phase (i.e., no terbinafine) was compared to the treatment phase (terbinafine), theophylline exposure (the area under the serum concentration-time curve from time zero to infinity) increased by 16% (P= 0.03), oral clearance decreased by 14% (P = 0.04), and half-life increased by 24% (P = 0.002). No significant changes in other theophylline pharmacokinetic parameters were evident.

scholarly journals Pharmacokinetic Interaction between Fosamprenavir-Ritonavir and Rifabutin in Healthy Subjects

2007 ◽  
Vol 52 (2) ◽  
pp. 534-538 ◽  
Author(s):  
Susan L. Ford ◽  
Ya-Chi Chen ◽  
Yu Lou ◽  
Julie Borland ◽  
Sherene S. Min ◽  
...  
Keyword(s):  
Steady State ◽  
Systemic Exposure ◽  
Pharmacokinetic Interaction ◽  
Concomitant Administration ◽  
Pharmacokinetic Parameters ◽  
Phosphate Ester ◽  
Open Label ◽  
Time Curve ◽  
Dosing Interval ◽  
Cyp3a4 Inhibitors

ABSTRACT Rifabutin (RFB) is administered for treatment of tuberculosis and Mycobacterium avium complex infection, including use for patients coinfected with human immunodeficiency virus (HIV). Increased systemic exposure to RFB and its equipotent active metabolite, 25-O-desacetyl-RFB (dAc-RFB), has been reported during concomitant administration of CYP3A4 inhibitors, including ritonavir (RTV), lopinavir, and amprenavir (APV); therefore, a reduction in the RFB dosage is recommended when it is coadministered with these protease inhibitors. Fosamprenavir (FPV), the phosphate ester prodrug of the HIV type 1 protease inhibitor APV, is administered either with or without RTV. A randomized, open-label, two-period, two-sequence, balanced, crossover drug interaction study was conducted with 22 healthy adult subjects to compare steady-state plasma RFB pharmacokinetic parameters during concomitant administration of FPV-RTV (700/100 mg twice a day [BID]) with a 75%-reduced RFB dose (150 mg every other day [QOD]) to the standard RFB regimen (300 mg once per day [QD]) by geometric least-squares mean ratios. Relative to results with RFB (300 mg QD), coadministration of dose-adjusted RFB with FPV-RTV resulted in an unchanged RFB area under the concentration-time curve for 0 to 48 h (AUC0-48) and a 14% decrease in the maximum concentration of drug in plasma (C max), whereas the AUC0-48 and C max of dAc-RFB were increased by 11- and 6-fold, respectively, resulting in a 64% increase in the total antimycobacterial AUC0-48. Relative to historical controls, the plasma APV AUC from 0 h to the end of the dosing interval (AUC0-τ) and C max were increased ∼35%, and the concentration at the end of the dosing interval at steady state was unchanged following coadministration of RFB with FPV-RTV. The safety profile of the combination of RFB and FPV-RTV was consistent with previously described events with RFB or FPV-RTV alone. Based on the results of this study, a reduction in the RFB dose by ≥75% (to 150 mg QOD or three times per week) is recommended when it is coadministered with FPV-RTV (700/100 mg BID).

Pharmacokinetics and Safety of Coadministered Oseltamivir and Rimantadine in Healthy Volunteers: An Open-Label, Multiple-Dose, Randomized, Crossover Study

2012 ◽  
Vol 52 (8) ◽  
pp. 1255-1264 ◽  
Author(s):  
Georgina Cirrincione-Dall ◽  
Barbara J. Brennan ◽  
Rosa M. Ballester-Sanchis ◽  
Mercidita T. Navarro ◽  
Brian E. Davies
Keyword(s):  
Crossover Study ◽  
Healthy Volunteers ◽  
Multiple Dose ◽  
Open Label ◽  
Randomized Crossover Study

scholarly journals Pharmacokinetics and pharmacodynamics of two multiple-dose piperacillin-tazobactam regimens.

1997 ◽  
Vol 41 (11) ◽  
pp. 2511-2517 ◽  
Author(s):  
D J Occhipinti ◽  
S L Pendland ◽  
L L Schoonover ◽  
E B Rypins ◽  
L H Danziger ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Dosage Regimen ◽  
Multiple Dose ◽  
Antimicrobial Agents ◽  
Plasma Concentrations ◽  
Culture Collection ◽  
Beta Lactam ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Time Curve ◽  
Bacteriological Response

The pharmacokinetics and pharmacodynamics of two multiple-dose regimens of piperacillin-tazobactam (3.375 g every 6 h and 4.5 g every 8 h) were evaluated at steady state for 12 healthy adult volunteers. Inhibitory and bactericidal activities for the two regimens were determined with five American Type Culture Collection (ATCC) organisms (Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Bacteroides fragilis). The percentage of time that plasma concentrations remained above the MIC (T > MIC) for each organism and dosage regimen was calculated. Areas under the inhibitory (AUIC0-24) and bactericidal activity (AUBC0-24) curves were calculated with the trapezoidal rule by using the reciprocal of the inhibitory and bactericidal titers determined for each dosage regimen. In order to assess the validity of predicted measures of bactericidal (AUC0-24/MBC) and inhibitory (AUC0-24/MIC) activity to determine bacteriological response to beta-lactam antimicrobial agents, AUC0-24/MBC and AUC0-24/MIC values were compared with measured AUBC0-24 and AUIC0-24 values. Total body clearance values were equivalent for piperacillin (183.96 +/- 22.66 versus 181.72 +/- 19.54 ml/min/1.73 m2, P > 0.05) and tazobactam (184.71 +/- 19.89 versus 184.87 +/- 18.35 ml/min/1.73 m2, P > 0.05) following the administration of the 3.375-g-every-6-h and 4.5-g-every-8-h dosages, respectively. Comparison of area under the plasma concentration-time curve (AUC0-24) for piperacillin (967.74 +/- 135.56 microg x h/ml versus 978.88 +/- 140.96 microg x h/ml) and tazobactam (120.14 +/- 15.78 microg x h/ml versus 120.01 +/- 16.22 microg x h/ml) revealed no significant differences (P > 0.05) between the 3.375-g-every-6-h and 4.5-g-every-8-h regimens, respectively. Both regimens provided T > MIC values of > 60% for all organisms tested. Measured values of bactericidal (AUBC) and inhibitory (AUIC) activity were significantly different (P < 0.05) from predicted values (AUC0-24/MBC and AUC0-24/MIC) for all organisms studied with the exception of the bactericidal activity for P. aeruginosa and S. aureus. Additionally, ATCC organisms possessing the same MICs and MBCs exhibited great differences in measured AUBC0-24 and AUIC0-24 values. Reasons for this difference may be inherent differences in organism specific susceptibility.

scholarly journals 81 Bioequivalence of a Manipulation-Resistant Immediate-Release Amphetamine Sulfate Formulation Compared with Reference Standard

CNS Spectrums ◽  
2019 ◽  
Vol 24 (1) ◽  
pp. 216-216
Author(s):  
Steve Caras ◽  
Terrilyn Sharpe
Keyword(s):  
Single Dose ◽  
Healthy Volunteers ◽  
Peak Concentration ◽  
Immediate Release ◽  
Open Label ◽  
Time Curve ◽  
Time To Peak ◽  
Amphetamine Sulfate ◽  
Quantifiable Concentration ◽  
Funding Acknowledgements

AbstractStudy ObjectivesWe compared the bioavailability of racemic amphetamine (d-amphetamine and l-amphetamine) from a manipulation-resistant immediate-release (IR) amphetamine sulfate capsule (AR19) versus amphetamine sulfate IR tablets (reference).MethodIn this open-label, randomized, two-period, two-treatment, two-sequence, crossover study, 36 healthy volunteers aged 18–45 received a single dose (20-mg capsule) of AR19 in one period and a single dose (2 x 10-mg tablets) of reference in another period, after a 10-hour overnight fast. Each drug administration was separated by a washout period of at least 6days. Bioequivalence for d- and l-amphetamine was assessed using time to peak concentration (Tmax), peak concentration in plasma (Cmax), and area under the plasma concentration–time curve from time-zero to the time of the last quantifiable concentration (AUClast) and extrapolated to infinity (AUCinf).ResultsAll 36 volunteers completed both treatment sequences. Mean (standard deviation; SD) Tmax for d- and l-amphetamine was similar for AR19 (2.84[1.05]; 3.05[1.22], respectively) and reference (2.52[0.75]; 2.75[1.00], respectively). The geometric least-squares mean ratios and 90% confidence intervals were within the boundary of 80%–125% for bioequivalence for Cmax (d-amphetamine, 98.35% [96.12–100.64]; l-amphetamine, 98.82% [96.42–101.28]), AUClast (d-amphetamine, 99.45% [96.92–102.05]; l-amphetamine, 99.29% [96.55–102.10]), and AUCinf (d-amphetamine, 99.50%[96.77–102.30]; l-amphetamine, 99.23% [96.06–102.50]). A total of 13 mild adverse events were reported by 7 volunteers (AEs; AR19, n=5; reference, n=8). No serious AEs were reported.ConclusionAR19 was well tolerated and was bioequivalent to reference when administered as a 20-mg dose in healthy volunteers.Funding Acknowledgements: This study was funded by Arbor Pharmaceuticals, LLC.

scholarly journals Opposite Effects of Single-Dose and Multidose Administration of the Ethanol Extract of Danshen on CYP3A in Healthy Volunteers

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Furong Qiu ◽  
Jian Jiang ◽  
Yueming Ma ◽  
Guangji Wang ◽  
Chenglu Gao ◽  
...  
Keyword(s):  
Single Dose ◽  
Healthy Volunteers ◽  
Plasma Concentrations ◽  
In Vitro Study ◽  
Ethanol Extract ◽  
Tanshinone Iia ◽  
Open Label ◽  
The Mean

The aim of this study was to investigate the effect of single- and multidose administration of the ethanol extract of danshen on in vivo CYP3A activity in healthy volunteers. A sequential, open-label, and three-period pharmacokinetic interaction study design was used based on 12 healthy male individuals. The plasma concentrations of midazolam and its metabolite 1-hydroxymidazolam were measured. Treatment with single dose of the extract caused the meanCmaxof midazolam to increase by 87% compared with control. After 10 days of the danshen extract intake, the mean AUC0–12,Cmax, andt1/2of midazolam were decreased by 79.9%, 66.6%, and 43.8%, respectively. The mean clearance of midazolam was increased by 501.6% compared with control. The in vitro study showed that dihydrotanshinone I in the extract could inhibit CYP3A, while tanshinone IIA and cryptotanshinone could induce CYP3A. In conclusion, a single-dose administration of the danshen extract can inhibit intestinal CYP3A, but multidose administration can induce intestinal and hepatic CYP3A.

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Anti-Vwf Nanobody® ALX-0681 After Single and Multiple Subcutaneous Administrations to Healthy Volunteers.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1063-1063 ◽  
Author(s):  
Khalid Abd-Elaziz ◽  
Pieter W. Kamphuisen ◽  
Christophe Lyssens ◽  
Mariska Reuvers ◽  
Izaak den Daas ◽  
...  
Keyword(s):  
Single Dose ◽  
Platelet Aggregation ◽  
Healthy Volunteers ◽  
Dose Level ◽  
Multiple Dose ◽  
Phase I Trial ◽  
Post Dose ◽  
Dose Cohort ◽  
Clinically Significant ◽  
Dose Levels

Abstract Abstract 1063 Poster Board I-85 ALX-0681 is a humanized bivalent Nanobody®, that binds to the A1 domain of von Willebrand factor (vWF) and hence blocks its interaction with platelet receptor GPIb-IX-V. Given its mode of action, ALX-0681 could provide an alternative treatment option for thrombotic thrombocytopenic purpura (TTP), a rare and life-threatening condition characterized by systemic platelet aggregation in the microcirculation mediated by activated vWF multimers. The goal of this Phase I trial in healthy volunteers was to determine the maximum tolerated dose (MTD) or biologically effective dose (BED) and the Phase II dosing and scheduling of ALX-0681, in order to support the further clinical development of ALX-0681 in TTP patients. In total, 36 healthy volunteers were included in this randomized, placebo-controlled study to evaluate the safety of single ascending doses and multiple doses of ALX-0681 administered subcutaneously (s.c.) (Table 1). Table 1 Dosing schedule for Phase I trial with ALX-0681 Cohort Dose (mg) Number of daily doses Subjects receiving ALX-0681 Subjects receiving placebo Single dose Cohort 1 2 1 3 1 Cohort 2 4 1 3 1 Cohort 3 8 1 3 1 Cohort 4 16 1 3 1 Cohort 5 10 1 3 1 Multiple dose Cohort 6 10 7 6 2 Cohort 7 10 14 6 2 Study endpoints included safety (dose limiting toxicities, adverse events (AEs) and immunogenicity), pharmacokinetics (PK), pharmacodynamics (PD) and pharmacological efficacy of ALX-0681. The latter endpoint was addressed by measuring the ristocetin cofactor (RICO) biomarker, reflecting vWF mediated inhibition of platelet aggregation. ALX-0681 was safe and well tolerated at all dose levels (Table 2). One unrelated SAE (meniscus lesion) occurred. The number of observed signs of bleeding and bruises increased with increasing treatment duration. However, all these events were of mild intensity. No signs of immunogenicity were observed for a minimum of 45 days after the last injection. Table 2 Summary of main safety results (number (%) of subjects with event) Dose level Subjects (n) AE SAE Bleeding Hematoma at injection site Hematoma at blood sampling site Other hematoma Single dose 2 mg 3 2 (67) 0 (0) 1 (33) 0 (0) 1 (33) 0 (0) 4 mg 3 2 (67) 0 (0) 1 (33) 0 (0) 0 (0) 0 (0) 8 mg 3 3 (100) 0 (0) 0 (0) 0 (0) 1 (33) 0 (0) 16 mg 3 3 (100) 0 (0) 0 (0) 0 (0) 0 (0) 1 (33) 10 mg 3 1 (33) 0 (0) 0 (0) 0 (0) 1 (33) 0 (0) Placebo 5 3 (60) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Multiple dose 10 mg (7d) 6 6 (100) 1 (17) 5 (83) 1 (17) 0 (0) 3 (50) Placebo (7d) 2 2 (100) 0 (0) 1 (50) 0 (0) 1 (50) 0 (0) 10 mg (14d) 6 6 (100) 0 (0) 5 (83) 5 (83) 4 (67) 5 (83) Placebo (14d) 2 2 (100) 0 (0) 1 (50) 0 (0) 0 (0) 0 (0) PK analysis showed a rapid increase in ALX-0681 plasma concentration (tmax = 4-10 h post dose), followed by a slow elimination phase (t1/2 = 10-78 h). All subjects dosed with ALX-0681 at 8 mg or higher showed complete inhibition of RICO activity to < 20% with an onset of 1-6 h post dose. This inhibition was maintained until 12-360 h post dose, depending on the dose level (Table 3). Overall, 20 (74%) and 17 (63%) of ALX-0681 treated subjects experienced a drop in vWF and FVIII levels below 50% of pre-dose levels, respectively. These events were all transient and not clinically significant. Table 3 Summary of main PD results (number (%) of subjects with event) Dose level Subjects (n) RICO < 20% vWF < 50% FVIII < 50% Subjects (%) Start (h)* Stop (h)* Single dose 2 mg 3 2 (67) 2-4 12-18 3 (100) 0 (0) 4 mg 3 2 (67) 4-6 18-36 1 (33) 1 (33) 8 mg 3 3 (100) 2-4 18-48 3 (100) 3 (100) 16 mg 3 3 (100) 1-4 48 0 (0) 2 (67) 10 mg 3 3 (100) 2-6 24-36 3 (100) 3 (100) Placebo 5 0 (0) NA NA 0 (0) 0 (0) Multiple dose 10 mg (7d) 6 6 (100) 2-4 168-192 5 (83) 3 (50) Placebo (7d) 2 0 (0) NA NA 0 (0) 0 (0) 10 mg (14d) 6 6 (100) 2-4 336-360 5 (83) 5 (83) Placebo (14d) 2 0 (0) NA NA 0 (0) 0 (0) * Time relative to first administration NA: not applicable In conclusion, ALX-0681 administered s.c. for up to 14 days was well tolerated and did not result in any clinically significant AEs. No local reactions, local intolerances or signs of clinically relevant bleeding were reported. The PD marker indicated complete inhibition of vWF mediated platelet aggregation following single daily s.c. injections of 10 mg, which was maintained over the 2 weeks treatment period. Multiple daily administration of s.c. injections of ALX-0681 did not result in an immunogenic reaction for a minimum of 45 days following completion of treatment. Based on the results of this study, ALX-0681 development will be advanced into a Phase II study in TTP patients to investigate the safety and efficacy of ALX-0681 in the target patient population. Disclosures: Abd-Elaziz: Ablynx NV: Consultancy. Kamphuisen:Ablynx NV: Consultancy. Lyssens:Ablynx NV: Employment. Reuvers:Ablynx NV: Consultancy. den Daas:Ablynx NV: Consultancy. Van Bockstaele:Ablynx NV: Employment. Vercruysse:Ablynx NV: Employment. Ulrichts:Ablynx NV: Employment. Baumeister:Ablynx NV: Employment. Crabbe:Ablynx NV: Employment. Compernolle:Ablynx NV: Employment. Holz:Ablynx NV: Employment.

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

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13512-e13512 ◽  
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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