Open-Label Pharmacokinetic of Oseltamivir in Healthy Obese Thai Adult Subjects

NCT01049763 | Completed Phase 1 DMC

• 1 other identifier: SEA 131
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

This study is planned to characterize the pharmacokinetic properties of oseltamivir and the active product--oseltamivir carboxylate--in obesity in order to provide clinical guidance for the optimum oseltamivir treatment regimens for severe influenza. It is also a prompt response to a new era influenza plan along with recognition of growing numbers of obese persons. The study findings will be available for a future management plan in dealing with this virus that is transmitted easily from person to person and has shown substantial antigenic changes over time. The primary focus of statistical analysis is to verify the effect of obesity on oseltamivir/oseltamivir carboxylate pharmacokinetics as measured by oseltamivir carboxylate Cmax, AUC (0-12), AUC (0-24), C12, λz, and t1/2 and oseltamivir Cmax, AUC (0-12), and C12.

Conditions

Healthy

Keywords

obese adult; non obese healthy volunteers; oseltamivir carboxylate; pharmacokinetics; healthy volunteers

Outcome Measures

Primary Outcomes (1)

• Oseltamivir carboxylate maximum concentration (OC Cmax) and area under the concentration curve 0-12h (OC AUC(0-12))

  12 hours

Secondary Outcomes (1)

• Oseltamivir maximum concentration at 12 hours (OS C12) Oseltamivir carboxylate area under the concentration curve 0-24 hours AUC(0-24)), concentration at 24 hours (C24), elimination rate constant (OC-λz), and elimination half life (t1/2)

  1 weeks

Study Arms (2)

Regimen A

EXPERIMENTAL

oseltamivir 75 mg single dose

Drug: oseltamivir

Regimen B

ACTIVE COMPARATOR

oseltamivir 150 mg single dose

Drug: oseltamivir

Interventions

oseltamivir DRUG

oseltamivir 150 mg single oral dose oseltamivir 75 mg single oral dose

Regimen A; Regimen B

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy as judged by a responsible physician with no abnormality identified on a medical evaluation including medical history and physical examination.
• Males and Females aged between 18 years to 60 years.
• BMI \>30 kg/ m2 (BMI = body weight \[BW\] (kg)/height (m2)) for obese group, BMI 18-24.9 kg/ m2 (BMI = BW (kg)/height (m2)) for control group.
• A female is eligible to enter and participate in this study if she is:
• of non-childbearing potential including pre-menopausal females with documented (medical report verification) hysterectomy or double oophorectomy
• or postmenopausal defined as 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum follicle stimulating hormone levels \>40 mIU/mL or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy
• or of childbearing potential, has a negative serum pregnancy test at screening and prior to start the study drug in each period, and abstain from sexual intercourse or agrees to using effective contraceptive methods during the study until completion of the follow-up procedures
• A male is eligible to enter and participate in this study if he: agrees to abstain from (or use a condom during) sexual intercourse with females of childbearing potential or lactating females; or is willing to use a condom/spermicide, during the study until completion of the follow-up procedures.
• Read, comprehend, and write at a sufficient level to complete study-related materials.
• Provide a signed and dated written informed consent prior to study participation.
• Normal electrocardiogram (ECG) with QTc \<450 msec.
• Willingness and ability to comply with the study protocol for the duration of the trial.

You may not qualify if:

• Females who are pregnant, trying to get pregnant, or are lactating.
• The subject has evidence of active substance abuse that may compromise safety, pharmacokinetics, or ability to adhere with protocol instructions.
• A positive pre-study hepatitis B surface antigen, positive hepatitis C antibody, or positive human immunodeficiency virus-1 (HIV-1) antibody result at screening.
• Subjects with a personal history of cardiac disease, symptomatic or asymptomatic arrhythmias, syncopal episodes, or additional risk factors for torsades de points (heart failure, hypokalemia).
• Subjects with a family history of sudden cardiac death.
• A creatinine clearance \<70 mL/min as determined by Cockcroft-Gault equation:
• CLcr (mL/min) = (140 - age) \* Wt / (72 \* Scr) (multiply answer by 0.85 for females). Where age is in years, weight (wt) is in kg, and serum creatinine (Scr) is in units of mg/dL \[Cockcroft, 1976\].
• History of alcohol or substance abuse or dependence within 6 months of the study: History of regular alcohol consumption averaging \>7 drinks/wk for women or \>14 drinks/wk for men. One drink is equivalent to 12 g alcohol = 5 oz (150 mL) of wine or 12 oz (360 mL) of beer or 1.5 oz (45 mL) of 80 proof distilled spirits within 6 months of screening.
• Use of prescription or non-prescription drugs except paracetamol at doses of up to 2 grams/day, including vitamins, herbal and dietary supplements within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication until the completion of the follow-up procedure.
• Use of live attenuated influenza vaccine, inactivated influenza vaccine, or any other antiinfluenza antiviral medications within 14 days prior to the first dose of investigational product.
• The subject has participated in a clinical trial and has received a drug or a new chemical entity within 30 days or 5 half lives, or twice the duration of the biological effect of any drug (whichever is longer) prior to the first dose of study medication.
• The subject is unwilling to abstain from ingesting alcohol within 48 hours prior to the first dose of study medication until collection of the final pharmacokinetic sample during each regimen.
• Subjects who have donated blood to the extent that participation in the study would result in more than 300 mL blood donated within a 30-day period.
• Subjects who have a history of allergy to the study drug or drugs of this class, or a history of drug or other allergy that, in the opinion of the investigator, contraindicates participation in the trial. In addition, if heparin is used during pharmacokinetic sampling, subjects with a history of sensitivity to heparin or heparin-induced thrombocytopenia should not be enrolled.
• Subjects with unstable medical conditions that, in the opinion of the investigator would compromise their participation in the trial

Sponsors & Collaborators

• South East Asia Infectious Disease Clinical Research Network: lead
• University of Oxford: collaborator

Study Sites (1)

Mahidol-Oxford Tropical Medicine Research Unit Faculty of Tropical Medicine, Mahidol University Bangkok

Bangkok, Thailand

Location

Related Publications (19)

• Ward P, Small I, Smith J, Suter P, Dutkowski R. Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic. J Antimicrob Chemother. 2005 Feb;55 Suppl 1:i5-i21. doi: 10.1093/jac/dki018.

  PMID: 15709056 BACKGROUND

• Tran TH, Nguyen TL, Nguyen TD, Luong TS, Pham PM, Nguyen vV, Pham TS, Vo CD, Le TQ, Ngo TT, Dao BK, Le PP, Nguyen TT, Hoang TL, Cao VT, Le TG, Nguyen DT, Le HN, Nguyen KT, Le HS, Le VT, Christiane D, Tran TT, Menno de J, Schultsz C, Cheng P, Lim W, Horby P, Farrar J; World Health Organization International Avian Influenza Investigative Team. Avian influenza A (H5N1) in 10 patients in Vietnam. N Engl J Med. 2004 Mar 18;350(12):1179-88. doi: 10.1056/NEJMoa040419. Epub 2004 Feb 25.

  PMID: 14985470 BACKGROUND

• Chotpitayasunondh T, Ungchusak K, Hanshaoworakul W, Chunsuthiwat S, Sawanpanyalert P, Kijphati R, Lochindarat S, Srisan P, Suwan P, Osotthanakorn Y, Anantasetagoon T, Kanjanawasri S, Tanupattarachai S, Weerakul J, Chaiwirattana R, Maneerattanaporn M, Poolsavathitikool R, Chokephaibulkit K, Apisarnthanarak A, Dowell SF. Human disease from influenza A (H5N1), Thailand, 2004. Emerg Infect Dis. 2005 Feb;11(2):201-9. doi: 10.3201/eid1102.041061.

  PMID: 15752436 BACKGROUND

• Treanor JJ, Hayden FG, Vrooman PS, Barbarash R, Bettis R, Riff D, Singh S, Kinnersley N, Ward P, Mills RG. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group. JAMA. 2000 Feb 23;283(8):1016-24. doi: 10.1001/jama.283.8.1016.

  PMID: 10697061 BACKGROUND

• Hayden FG, Treanor JJ, Fritz RS, Lobo M, Betts RF, Miller M, Kinnersley N, Mills RG, Ward P, Straus SE. Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment. JAMA. 1999 Oct 6;282(13):1240-6. doi: 10.1001/jama.282.13.1240.

  PMID: 10517426 BACKGROUND

• Hayden FG, Atmar RL, Schilling M, Johnson C, Poretz D, Paar D, Huson L, Ward P, Mills RG. Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza. N Engl J Med. 1999 Oct 28;341(18):1336-43. doi: 10.1056/NEJM199910283411802.

  PMID: 10536125 BACKGROUND

• de Jong MD, Tran TT, Truong HK, Vo MH, Smith GJ, Nguyen VC, Bach VC, Phan TQ, Do QH, Guan Y, Peiris JS, Tran TH, Farrar J. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med. 2005 Dec 22;353(25):2667-72. doi: 10.1056/NEJMoa054512.

  PMID: 16371632 BACKGROUND

• Yen HL, Ilyushina NA, Salomon R, Hoffmann E, Webster RG, Govorkova EA. Neuraminidase inhibitor-resistant recombinant A/Vietnam/1203/04 (H5N1) influenza viruses retain their replication efficiency and pathogenicity in vitro and in vivo. J Virol. 2007 Nov;81(22):12418-26. doi: 10.1128/JVI.01067-07. Epub 2007 Sep 12.

  PMID: 17855542 BACKGROUND

• Yen HL, Monto AS, Webster RG, Govorkova EA. Virulence may determine the necessary duration and dosage of oseltamivir treatment for highly pathogenic A/Vietnam/1203/04 influenza virus in mice. J Infect Dis. 2005 Aug 15;192(4):665-72. doi: 10.1086/432008. Epub 2005 Jul 15.

  PMID: 16028136 BACKGROUND

• Cockshott WP, Thompson GT, Howlett LJ, Seeley ET. Intramuscular or intralipomatous injections? N Engl J Med. 1982 Aug 5;307(6):356-8. doi: 10.1056/NEJM198208053070607. No abstract available.

  PMID: 7088101 BACKGROUND

• Ritschel WA, Kaul S. Prediction of apparent volume of distribution in obesity. Methods Find Exp Clin Pharmacol. 1986 Apr;8(4):239-47.

  PMID: 3724300 BACKGROUND

• Abernethy DR, Greenblatt DJ. Drug disposition in obese humans. An update. Clin Pharmacokinet. 1986 May-Jun;11(3):199-213. doi: 10.2165/00003088-198611030-00002.

  PMID: 3524955 BACKGROUND

• Beckel MH. Factor affecting the storage of drug and other xenobiotics in adipose tissue. Adv Drug Res 1994; 25: 55-86.

  BACKGROUND

• Benedek IH, Blouin RA, McNamara PJ. Serum protein binding and the role of increased alpha 1-acid glycoprotein in moderately obese male subjects. Br J Clin Pharmacol. 1984 Dec;18(6):941-6. doi: 10.1111/j.1365-2125.1984.tb02567.x.

  PMID: 6529534 BACKGROUND

• Caraco Y, Zylber-Katz E, Berry EM, Levy M. Antipyrine disposition in obesity: evidence for negligible effect of obesity on hepatic oxidative metabolism. Eur J Clin Pharmacol. 1995;47(6):525-30. doi: 10.1007/BF00193706.

  PMID: 7768256 BACKGROUND

• Stokholm KH, Brochner-Mortensen J, Hoilund-Carlsen PF. Increased glomerular filtration rate and adrenocortical function in obese women. Int J Obes. 1980;4(1):57-63.

  PMID: 7390700 BACKGROUND

• Wattanagoon Y, Stepniewska K, Lindegardh N, Pukrittayakamee S, Silachamroon U, Piyaphanee W, Singtoroj T, Hanpithakpong W, Davies G, Tarning J, Pongtavornpinyo W, Fukuda C, Singhasivanon P, Day NP, White NJ. Pharmacokinetics of high-dose oseltamivir in healthy volunteers. Antimicrob Agents Chemother. 2009 Mar;53(3):945-52. doi: 10.1128/AAC.00588-08. Epub 2008 Dec 22.

  PMID: 19104028 BACKGROUND

• Massarella JW, He GZ, Dorr A, Nieforth K, Ward P, Brown A. The pharmacokinetics and tolerability of the oral neuraminidase inhibitor oseltamivir (Ro 64-0796/GS4104) in healthy adult and elderly volunteers. J Clin Pharmacol. 2000 Aug;40(8):836-43. doi: 10.1177/00912700022009567.

  PMID: 10934667 BACKGROUND

• Jittamala P, Pukrittayakamee S, Tarning J, Lindegardh N, Hanpithakpong W, Taylor WR, Lawpoolsri S, Charunwattana P, Panapipat S, White NJ, Day NP. Pharmacokinetics of orally administered oseltamivir in healthy obese and nonobese Thai subjects. Antimicrob Agents Chemother. 2014;58(3):1615-21. doi: 10.1128/AAC.01786-13. Epub 2013 Dec 23.

  PMID: 24366750 DERIVED

MeSH Terms

Interventions

Oseltamivir

Intervention Hierarchy (Ancestors)

Acetamides; Amides; Organic Chemicals; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons

Study Officials

• Podjanee Jittmala, MD

  Mahidol-Oxford Tropical Medicine Research Unit Faculty of Tropical Medicine, Mahidol University

  PRINCIPAL INVESTIGATOR

• Sasithon Pukrittayakamee, Professor

  Mahidol University

  STUDY CHAIR

• Pratap Singhasivanon, A/Professor

  Mahidol University

  STUDY CHAIR

• Nick White, Professor

  Mahidol-Oxford Tropical Medicine Research Unit Faculty of Tropical Medicine, Mahidol University Bangkok, Thailand

  STUDY CHAIR

• Nick Day, Professor

  Mahidol-Oxford Tropical Medicine Research Unit Faculty of Tropical Medicine, Mahidol University Bangkok, Thailand

  STUDY CHAIR

• Niklas Lindegardh, A/Professor

  Clinical Pharmacology Laboratory Faculty of Tropical Medicine, Mahidol University Bangkok, Thailand

  STUDY CHAIR

• Bob Taylor, MD

  Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University Bangkok, Thailand

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Intervention Model: CROSSOVER
• Sponsor Type: NETWORK

Study Record Dates

• First Submitted: January 13, 2010
• First Posted: January 14, 2010
• Study Start: January 1, 2010
• Primary Completion: September 1, 2010
• Study Completion: October 1, 2010
• Last Updated: October 8, 2010

Record last verified: 2010-10

Locations

TH (1)