A Study of the Pharmacology of Oseltamivir (Tamiflu) in Pregnancy

Pregnancy Clinical Trial

Official title:

A Study of the Pharmacology of Oseltamivir (Tamiflu) in Pregnancy

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT00873886
• Other study ID #: IRB #PRO07080362
• Secondary ID: 5U10HD047905-02
• Status: Withdrawn
• Phase: Phase 1
• First received: April 1, 2009
• Last updated: September 28, 2015
• Start date: April 2009
• Est. completion date: September 2010

Study information

• Verified date: September 2015
• Source: University of Pittsburgh
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The primary research question of this study is: Does the pharmacokinetics of oseltamivir after a single oral dose differ between the pregnant and non-pregnant women?

Description:

With the pending threat of pandemic avian influenza, the disproportionate morbidity and mortality documented in previous 20th century pandemics among pregnant women, and the lack of any data for use of these vital antiviral drugs in pregnancy, study of the pharmacology of oseltamivir in pregnancy is imperative. If and when the next pandemic occurs, a better understanding of this drug's safety and pharmacologic profiles for use in pregnancy is critical given the fact that it will be used in this vulnerable patient population.

This is a pilot study of the use of oseltamivir in pregnancy. This data will be combined with data from the parallel Pediatric Pharmacology Research Unit (PPRU) studies to put together a portfolio for use in understudied populations. This will allow for a re-thinking of the current status and potentially allow for small trials to be performed with patients who are suffering from influenza in pregnancy, to assess efficacy. The relevance with the pandemic strain and its corresponding Minimum Inhibitory Concentration (MIC) may have direct implications for dosing in pregnancy if lower levels of drug are documented. In addition, depending on the findings from the esterase component of the investigation, future investigation into mechanistic bases for changes in enzyme activity are possible.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: September 2010
• Est. primary completion date: September 2010
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• For Oseltamivir (Tamiflu) arm:

• Singleton gestation prior to 24 0/7 weeks gestation

• Planning to undergo a termination procedure for the incident pregnancy

• Willingness to take the single-dose medication and to follow study procedures

• Able to undergo informed consent.

• For Esterase arm:

• Singleton gestation greater than 32 completed weeks and less than 40 completed weeks of gestation

• Absence of severe pregnancy complication that could affect body volume and or metabolism (i.e., preeclampsia, renal dysfunction, hepatic dysfunction [defined as serum creatinine clearance of < 30 ml/min or a known ALT/AST> 2x facility normal value], etc.)

• Willingness to follow study procedures

• Able to undergo informed consent

• The use of medications that may affect renal metabolism is not a contraindication to participation since these subjects are only undergoing PK sampling.

Exclusion Criteria:

• For Oseltamivir (Tamiflu) arm:

• Known current in utero fetal death

• Significant medical history and/or medication use as determined by the investigator that has the potential to affect results of the study or put the patient at risk from the single-dosing

• Known hypersensitivity to the components of the study drug

• Known hepatic or renal dysfunction (defined as serum creatinine clearance of < 30 ml/min or a known ALT/AST> 2x facility normal value)

• Chronic use of street drugs (obtained via subject interview and/or medical history)

• Participation in any other concurrent interventional study.

• We will ask if they have a history of depression in the past requiring treatment or if they are currently actively depressed. If either of these questions yields a positive response, we will not consider the patient eligible and will not enroll the subject.

• For Esterase arm:

• Known current in utero fetal death

• Significant medical history as determined by the investigator to potentially affect results of the study

• Chronic use of street drugs (obtained via subject interview and/or medical history

• Participation in any other concurrent interventional study.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Influenza
• Pregnancy

Intervention

Drug:
• Oseltamivir (Tamiflu)
The following procedures will be performed on two occasions: once at least three days prior to the scheduled pregnancy termination procedure and again about eight weeks after the termination procedure. A) Subject will take 75 mg of oseltamivir pill by mouth B) Multiple blood draws (1 teaspoon each) over the next 48 hours after taking oseltamivir. Urine samples also will be collected.

Procedure:
• Blood Draws
Two blood draws (1 teaspoon each) will be performed: once during third trimester of pregnancy and again about eight weeks after delivery.

Locations

Country	Name	City	State
United States	Magee-Womens Hospital of University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania

Sponsors (3)

Lead Sponsor	Collaborator
University of Pittsburgh	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

References & Publications (16)

Advisory Committee on Immunization Practices, Smith NM, Bresee JS, Shay DK, Uyeki TM, Cox NJ, Strikas RA. Prevention and Control of Influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006 Jul 28;55(RR-10):1-42. Erratum in: MMWR Morb Mortal Wkly Rep. 2006 Jul 28;55(29):800. — View Citation

Cox S, Posner SF, McPheeters M, Jamieson DJ, Kourtis AP, Meikle S. Hospitalizations with respiratory illness among pregnant women during influenza season. Obstet Gynecol. 2006 Jun;107(6):1315-22. — View Citation

Cox S, Posner SF, McPheeters M, Jamieson DJ, Kourtis AP, Meikle S. Influenza and pregnant women: hospitalization burden, United States, 1998-2002. J Womens Health (Larchmt). 2006 Oct;15(8):891-3. — View Citation

Dutkowski R, Thakrar B, Froehlich E, Suter P, Oo C, Ward P. Safety and pharmacology of oseltamivir in clinical use. Drug Saf. 2003;26(11):787-801. Review. — View Citation

Ferguson NM, Cummings DA, Cauchemez S, Fraser C, Riley S, Meeyai A, Iamsirithaworn S, Burke DS. Strategies for containing an emerging influenza pandemic in Southeast Asia. Nature. 2005 Sep 8;437(7056):209-14. Epub 2005 Aug 3. — View Citation

Garcia-Sastre A, Whitley RJ. Lessons learned from reconstructing the 1918 influenza pandemic. J Infect Dis. 2006 Nov 1;194 Suppl 2:S127-32. — View Citation

Hayden FG, Treanor JJ, Betts RF, Lobo M, Esinhart JD, Hussey EK. Safety and efficacy of the neuraminidase inhibitor GG167 in experimental human influenza. JAMA. 1996 Jan 24-31;275(4):295-9. — View Citation

Health Sciences Authority. Product Safety Alert: new preclinical findings on Oseltamivir. March 2004. (Accessed November 27, 2006 at: http://www.hsa.gov.sg/docs/safetyalert_oseltamivir_March04.pdf.)

Influenza vaccination and treatment during pregnancy. ACOG Committee Opinion No. 305. American College of Obstetricians and Gynecologists. Obstet Gynecol 2004;104:1125-6.

Irving WL, James DK, Stephenson T, Laing P, Jameson C, Oxford JS, Chakraverty P, Brown DW, Boon AC, Zambon MC. Influenza virus infection in the second and third trimesters of pregnancy: a clinical and seroepidemiological study. BJOG. 2000 Oct;107(10):1282-9. — View Citation

Lindsay L, Jackson LA, Savitz DA, Weber DJ, Koch GG, Kong L, Guess HA. Community influenza activity and risk of acute influenza-like illness episodes among healthy unvaccinated pregnant and postpartum women. Am J Epidemiol. 2006 May 1;163(9):838-48. Epub 2006 Mar 22. — View Citation

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. — View Citation

Moscona A. Neuraminidase inhibitors for influenza. N Engl J Med. 2005 Sep 29;353(13):1363-73. Review. — View Citation

Neuzil KM, Reed GW, Mitchel EF, Simonsen L, Griffin MR. Impact of influenza on acute cardiopulmonary hospitalizations in pregnant women. Am J Epidemiol. 1998 Dec 1;148(11):1094-102. — View Citation

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. Review. — View Citation

Webster RG, Govorkova EA. H5N1 influenza--continuing evolution and spread. N Engl J Med. 2006 Nov 23;355(21):2174-7. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in the area under the concentration vs. time curve (AUC 0-7 d) in the first and second trimesters of pregnancy with comparisons to the post-termination non-pregnant follow-up data on these enrollees and historical non-pregnant data.		Less than 9 weeks for subjects planning termination; up to 5 months for subjects enrolled during their 3rd trimester.	No
Secondary	Non-compartmental model analysis for Cmax, Tmax, Cl/F, Clr,V/F, MRT and t ½.		Less than 9 weeks for subjects planning termination; up to 5 months for subjects enrolled during their 3rd trimester.	No
Secondary	Plasma concentrations of oseltamivir after single-dosing.		Less than 9 weeks for subjects planning termination; up to 5 months for subjects enrolled during their 3rd trimester.	No
Secondary	Evaluation of carboxy-esterase levels and activity in all trimesters of pregnancy with comparison to the post-partum internal controls.		Less than 9 weeks for subjects planning termination; up to 5 months for subjects enrolled during their 3rd trimester.	No
Secondary	Tolerance (side effect profile) of single-dose oseltamivir in pregnancy.		Less than 9 weeks for subjects planning termination; up to 5 months for subjects enrolled during their 3rd trimester.	Yes