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PHARMACOKINETICS
AND
PHARMACOGENOMICS
OF
ONCE
DAILY
RALTEGRAVIR
AND
ATAZANAVIR
IN
HEALTHY
VOLUNTEERS
by
Michael
Neely
A
Thesis
Presented
to
the
FACULTY
OF
THE
USC
GRADUATE
SCHOOL
UNIVERSITY
OF
SOUTHERN
CALIFORNIA
In
Partial
Fulfillment
of
the
Requirements
for
the
Degree
MASTER
OF
SCIENCE
(MEDICINE)
May
2011
Copyright
2011
Michael
Neely
Object Description
| Title | Pharmacokinetics and pharmacogenomics of once daily raltegravir and atazanavir in healthy volunteers |
| Author | Neely, Michael |
| Author email | mneely@usc.edu; mnneely@gmail.com |
| Degree | Master of Science |
| Document type | Thesis |
| Degree program | Clinical & Biomedical Investigations |
| School | Keck School of Medicine |
| Date defended/completed | 2011-02-02 |
| Date submitted | 2011 |
| Restricted until | Unrestricted |
| Date published | 2011-02-03 |
| Advisor (committee chair) | Jelliffe, Roger |
| Advisor (committee member) |
Schumitzky, Alan Azen, Stanley Paul |
| Abstract | Introduction: Atazanavir inhibits UDP-glucuronyl-transferase-1A1 (UGT1A1), which metabolizes raltegravir, but the magnitude of steady-state inhibition and role of UGT1A1 genotype is unknown. Sufficient inhibition could lead to reduced-dose and -cost raltegravir regimens. Methods: Nineteen healthy volunteers, age 24 – 51 years, took raltegravir 400 mg twice daily (treatment Arm A) and raltegravir 400 mg plus atazanavir 400 mg once daily (treatment Arm B). Each treatment arm was separated by ≥3 days. After one week on each regimen, raltegravir and raltegravir-glucuronide plasma and urine concentrations were measured by liquid chromatography-tandem mass spectrometry in multiple samples obtained over 12 hours (Arm A) or 24 hours (Arm B) and analyzed by non-compartmental methods. UGT1A1 promoter variants were detected with a commercially available kit and published primers. The primary outcome was the ratio of plasma raltegravir Ctau, or concentration at the end of the dosing interval for Arm B (24 hours) vs. Arm A (12 hours). Frequentist and Bayesian distributions of this ratio were compared. Results: The Arm B to Arm A geometric mean ratios (GMR) and 95% confidence intervals for plasma raltegravir Ctau, AUC0-12, and raltegravir-glucuronide:raltegravir AUC0-12 were 0.38 (0.22 – 0.65), 1.32 (0.62 – 2.81), and 0.47 (0.38 – 0.59), respectively. Using results from a previously published study of single-dose raltegravir added to atazanavir as a prior distribution, the Bayesian posterior GMR and 95% credibility interval for the Arm B to Arm A Ctau ratio was 0.28 (0.19 – 0.41). Nine volunteers were heterozygous and one was homozygous for a UGT1A1 reduction-of-function allele, but these were not associated with metabolite formation.; Conclusions: Although atazanavir significantly reduced formation of the glucuronide metabolite, its steady-state boosting of plasma raltegravir did not render Ctau with a once-daily raltegravir dose of 400 mg similar to Ctau with the standard twice-daily dose, regardless of frequentist or Bayesian analytic methods. UGT1A1 promoter variants did not significantly influence this interaction. |
| Keyword | pharmacokinetics; pharmacogenomics; raltegravir; atazanavir; Bayesian |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m3641 |
| Contributing entity | University of Southern California |
| Rights | Neely, Michael |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | cisadmin@dots.usc.edu |
| Filename | etd-Neely-4261 |
| Archival file | uscthesesreloadpub_Volume29/etd-Neely-4261.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@dots.usc.edu |
| Full text | PHARMACOKINETICS AND PHARMACOGENOMICS OF ONCE DAILY RALTEGRAVIR AND ATAZANAVIR IN HEALTHY VOLUNTEERS by Michael Neely A Thesis Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree MASTER OF SCIENCE (MEDICINE) May 2011 Copyright 2011 Michael Neely |
