A Randomized, Open-label Study of the Pharmacokinetics and Safety of Oral and Intravenous Administration of Omadacycline to Healthy Subjects

Omadacycline is a first in class aminomethylcycline antibiotic with microbiological activity against Gram-positive and Gram-negative aerobes and anaerobes, and atypical bacteria that is being developed for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). The bioavailability of a Phase 3 tablet formulation relative to intravenous (IV) administration (and of other oral formulations relative to the Phase 3 tablet) was investigated in an open-label, randomized, four-period, crossover study in healthy subjects age 18-50 years. Subjects received omadacycline 100 mg IV, 300 mg oral as two different tablet formulations with different dissolution profiles, and a 300 mg as an oral solution. Plasma omadacycline concentrations were determined using a validated LC/MS/MS method. Twenty of 24 subjects completed all treatment periods. Both tablet formulations produced equivalent total exposure relative to each other. The Phase 3 tablet produced equivalent exposure to the 100 mg IV dose with geometric mean ratio (90% confidence intervals [CI]) for AUCinfof 1.00 (0.93,1.07). Absolute bioavailability of the tablets was approximately 34.5%. Intersubject variability was consistent among the oral formulations (∼20-25%). Single oral and IV doses of omadacycline were well tolerated; three subjects experienced mild adverse events (dizziness, nausea, vomiting) that resolved without intervention. A 300 mg dose of the tablet formulation of omadacycline intended for use in phase 3 studies produced total exposure equivalent to that of a 100 mg IV dose.

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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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A Phase 3, Randomized, Open-label, Noninferiority Trial Evaluating Anti-Rabies Monoclonal Antibody Cocktail (TwinrabTM) Against Human Rabies Immunoglobulin (HRIG)

Clinical Infectious Diseases ◽

10.1093/cid/ciaa779 ◽

2020 ◽

Cited By ~ 1

Author(s):

Kevinkumar Kansagra ◽

Deven Parmar ◽

Sanjeev Kumar Mendiratta ◽

Jatin Patel ◽

Shuchi Joshi ◽

...

Keyword(s):

Monoclonal Antibody ◽

Neutralizing Antibodies ◽

Geometric Mean ◽

World Health ◽

Human Rabies ◽

Open Label ◽

Phase 3 ◽

Noninferiority Trial ◽

Rabid Animal ◽

Antibody Cocktail

Abstract Background Limited supply, cost and potential for severe adverse effects observed with the blood derived rabies immunoglobulin products has led to search for alternative therapies. This issue has been addressed by developing an anti-rabies monoclonal antibody cocktail. Methods This is a phase 3, randomized, open-label, noninferiority trial conducted in patients with World Health Organization (WHO) category III exposure with suspected rabid animal. Eligible patients were assigned to either the test arm, TwinrabTM (docaravimab and miromavimab) or the reference arm, human rabies immunoglobulin (HRIG; Imogam® Rabies-HT), in a ratio of 1:1. The primary endpoint was the comparison of responder rates between the 2 arms assessed as percentage of those with rabies virus neutralizing antibodies titers ≥0.5 IU/mL on day 14. Results A total of 308 patients were equally randomized into the 2 arms. In the per-protocol (PP) population, there were 90.21% responders in the TwinrabTM arm and 94.37% in the HRIG arm. The geometric mean of rapid fluorescent foci inhibition test titers in the PP on day 14 were 4.38 and 4.85 IU/mL, for the TwinrabTM and HRIG arms, respectively. There were no deaths or serious adverse events reported. Conclusions This study confirmed that TwinrabTM is noninferior to HRIG in terms of providing an unbroken window of protection up to day 84. This trial in healthy adults with WHO category III exposure from suspected rabid animal also establishes the safety of TwinrabTM in patients with 1 WHO approved vaccine regimen (Essen). Clinical Trials Registration CTRI/2017/07/009038.

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A randomized, open-label, crossover study to compare the safety and pharmacokinetics of two tablet formulations of tenofovir (tenofovir disoproxil and tenofovir disoproxil fumarate) in healthy subjects

International Journal of Clinical Pharmacology and Therapeutics ◽

10.5414/cp203651 ◽

2020 ◽

Vol 58 (12) ◽

pp. 749-756

Author(s):

Jae Nam Yun ◽

Ji-Sun Yeun ◽

Hye-Su Kan ◽

Minyu Lee ◽

Namsick Kim ◽

...

Keyword(s):

Crossover Study ◽

Tenofovir Disoproxil Fumarate ◽

Healthy Subjects ◽

Open Label ◽

Tablet Formulations

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Assessment of Pharmacodynamic Equivalence and Tolerability of Lanthanum Carbonate Oral Powder and Tablet Formulations: A Single-Center, Randomized, Open-Label, 2-Period Crossover Study in Healthy Subjects

Clinical Therapeutics ◽

10.1016/j.clinthera.2012.05.003 ◽

2012 ◽

Vol 34 (6) ◽

pp. 1290-1300.e2 ◽

Cited By ~ 6

Author(s):

David Pierce ◽

Stuart Hossack ◽

Antoine Robinson ◽

Pinggao Zhang ◽

Patrick Martin

Keyword(s):

Crossover Study ◽

Healthy Subjects ◽

Lanthanum Carbonate ◽

Single Center ◽

Open Label ◽

Tablet Formulations

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Bioavailability of Three Rufinamide Oral Suspensions Compared With the Marketed 400-mg Tablet Formulation: Results From a Randomized-Sequence, Open-Label, Four-Period, Four-Sequence Crossover Study in Healthy Subjects

Clinical Therapeutics ◽

10.1016/j.clinthera.2011.01.016 ◽

2011 ◽

Vol 33 (1) ◽

pp. 146-157 ◽

Cited By ~ 6

Author(s):

David John Critchley ◽

Jagadeesh Aluri ◽

Peter Boyd ◽

Matthew Whayman ◽

Milind Narurkar ◽

...

Keyword(s):

Crossover Study ◽

Healthy Subjects ◽

Tablet Formulation ◽

Open Label

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A Phase 1, Open-Label Study in Healthy Subjects to Evaluate the Absolute Bioavailability of AG-221 by a Microtracer Approach

Oncology and Therapy ◽

10.1007/s40487-019-0097-7 ◽

2019 ◽

Vol 8 (1) ◽

pp. 91-102

Author(s):

Xiaomin Wang ◽

Jian Chen ◽

Josephine Reyes ◽

Simon Zhou ◽

Maria Palmisano ◽

...

Keyword(s):

Healthy Subjects ◽

Phase 1 ◽

Absolute Bioavailability ◽

Open Label ◽

Open Label Study ◽

Label Study ◽

The Absolute

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A Phase 1, Single-Center, Single-Dose, Open-Label, Randomized, Crossover, Comparative Bioavailability And Food Effect Study To Compare BPS-314d-MR 15 µg And 60 µg Tablet Formulations To The Existing BPS-MR 60 µg Tablet Formulation In Healthy Volunteers

10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a4784 ◽

2012 ◽

Author(s):

David W. Armstrong ◽

William Wargin ◽

David Mottola ◽

Eugene J. Sullivan

Keyword(s):

Single Dose ◽

Healthy Volunteers ◽

Food Effect ◽

Phase 1 ◽

Effect Study ◽

Tablet Formulation ◽

Single Center ◽

Open Label ◽

Comparative Bioavailability ◽

Tablet Formulations

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Pharmacokinetic Interaction between Maraviroc and Fosamprenavir-Ritonavir: an Open-Label, Fixed-Sequence Study in Healthy Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01098-13 ◽

2013 ◽

Vol 57 (12) ◽

pp. 6158-6164 ◽

Cited By ~ 5

Author(s):

Manoli Vourvahis ◽

Anna Plotka ◽

Laure Mendes da Costa ◽

Annie Fang ◽

Jayvant Heera

Keyword(s):

Healthy Subjects ◽

Geometric Mean ◽

Active Form ◽

Pharmacokinetic Interaction ◽

Pharmacokinetic Parameters ◽

Maximum Plasma ◽

Open Label ◽

Fixed Sequence ◽

Dosing Interval ◽

Period 2

ABSTRACTThis open-label, fixed-sequence, phase 1 study evaluated the pharmacokinetic interaction between maraviroc (MVC) and ritonavir-boosted fosamprenavir (FPV/r) in healthy subjects. In period 1, subjects received 300 mg of MVC twice daily (BID; cohort 1) or once daily (QD; cohort 2) for 5 days. In period 2, cohort 1 subjects received 700/100 mg of FPV/r BID alone on days 1 to 10 and then FPV/r at 700/100 mg BID plus MVC at 300 mg BID on days 11 to 20; cohort 2 subjects received FPV/r at 1,400/100 mg QD alone on days 1 to 10 and then FPV/r at 1,400/100 mg QD plus MVC at 300 mg QD on days 11 to 20. Pharmacokinetic parameters, assessed on day 5 of period 1 and on days 10 and 20 of period 2, included the maximum plasma concentration (Cmax), the concentration at end of dosing interval (Cτ), and the area under the curve over dosing interval (AUCτ). Safety and tolerability were also assessed. MVC geometric mean AUCτ,Cmax, andCτwere increased by 149, 52, and 374%, respectively, after BID dosing with FPV/r, and by 126, 45, and 80%, respectively, after QD dosing. Amprenavir (the active form of the prodrug fosamprenavir) and ritonavir exposures were decreased in the presence of MVC with amprenavir AUCτ,Cmax, andCτdecreased by 34 to 36% in the presence of FPV/r plus maraviroc BID and by 15 to 30% with FPV/r plus MVC QD both compared to FPV/r alone. The overall all-causality adverse-event (AE) incidence rate was 96.4%; all AEs were of mild or moderate severity. Commonly reported treatment-related AEs (>20% of patients overall) included diarrhea, fatigue, abdominal discomfort, headache, and nausea. No serious AEs or deaths occurred. In summary, maraviroc exposure increased in the presence of FPV/r, whereas MVC coadministration decreased amprenavir and ritonavir exposures. MVC dosed at 300 mg BID with FPV/r is not recommended due to concerns of lower amprenavir exposures; however, no dose adjustment is warranted with MVC at 150 mg BID in combination with FPV/r based on the available clinical data. MVC plus FPV/r was generally well tolerated; no new safety signals were detected.

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Evaluation of Doravirine Pharmacokinetics When Switching from Efavirenz to Doravirine in Healthy Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01757-16 ◽

2016 ◽

Vol 61 (2) ◽

Cited By ~ 16

Author(s):

Ka Lai Yee ◽

Rosa I. Sanchez ◽

Patrice Auger ◽

Rachael Liu ◽

Li Fan ◽

...

Keyword(s):

Plasma Concentration ◽

Healthy Subjects ◽

Geometric Mean ◽

Transcriptase Inhibitor ◽

Open Label ◽

Genetic Barrier ◽

Fixed Sequence ◽

Time Curve ◽

Cyp3a4 Substrate

ABSTRACT Doravirine is a novel, potent nonnucleoside reverse transcriptase inhibitor (NNRTI) for the treatment of patients with human immunodeficiency virus type 1 (HIV-1) infection that demonstrates a high genetic barrier to resistance and that has been well tolerated in studies to date. Doravirine is a candidate for patients switching from less-well-tolerated NNRTIs, such as efavirenz. While doravirine is a cytochrome P450 3A4 (CYP3A4) substrate, efavirenz induces CYP3A4; therefore, the pharmacokinetics of both drugs following a switch from efavirenz to doravirine were assessed. This was a 3-period, fixed-sequence, open-label study. Healthy adults were dosed with doravirine at 100 mg for 5 days once daily (QD) (period 1). Following a 7-day washout, efavirenz was administered at 600 mg QD for 14 days (period 2). Subsequently, doravirine was administered at 100 mg QD for 14 days (period 3). Blood samples were collected for pharmacokinetic analyses. Twenty healthy subjects were enrolled, and 17 completed the study. One day after efavirenz cessation, the doravirine area under the concentration-time curve from predosing to 24 h postdosing (AUC0–24), maximum observed plasma concentration (C max), and observed plasma concentration at 24 h postdosing (C 24) were reduced by 62%, 35%, and 85%, respectively, compared with the values with no efavirenz pretreatment. These decreases recovered to 32%, 14%, and 50% for AUC0–24, C max, and C 24, respectively, by day 14 after efavirenz cessation. The doravirine C 24 reached projected therapeutic trough concentrations, based on in vitro efficacy, on day 2 following efavirenz cessation. Geometric mean efavirenz concentrations were 3,180 ng/ml on day 1 and 95.7 ng/ml on day 15, and efavirenz was present at therapeutic concentrations (>1,000 ng/ml) until day 4. Though doravirine exposure was transiently decreased following efavirenz treatment cessation, dose adjustment may not be necessary to maintain therapeutic concentrations of at least one drug during switching in a virologically suppressed population.

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