Population Pharmacokinetics and Pharmacodynamics of Zidovudine in HIV‐Infected Infants and Children

The purpose of this study was to assess the population pharmacokinetics (PK) and pharmacodynamics (PD) of zidovudine (ZDV) in infants and children. This evaluation includes 394 subjects who participated in Pediatric AIDS Clinical Trials Group (PACTG) Study 152 and received either ZDV alone or in combination with didanosine. The most significant PK covariate was age, with infants < 2 years of age having reduced size‐adjusted clearance. ZDV exposure was weakly related to maximal reduction in immune complex‐dissociated (ICD) p24 antigen but not to reduction at 6 months. Mild chronic anemia occurred in 7.6% of subjects with ZDV average concentration < 1.3 μM (350 ng/mL) versus in 23.4% subjects with higher ZDV concentrations (p < 0.001). There was a direct linear relationship between hemoglobin and ZDV levels. It was concluded that ZDV oral clearance is reduced in infants compared to older children. This lower clearance leads to higher ZDV exposure in infants and contributes to increased hematologic toxicity.

[1]  Lewis B. Sheiner,et al.  Some suggestions for measuring predictive performance , 1981, Journal of Pharmacokinetics and Biopharmaceutics.

[2]  J. Golmard,et al.  Clinical pharmacokinetics of zidovudine: inter and intraindividual variability and relationship to long term efficacy and toxicity , 2004, European Journal of Clinical Pharmacology.

[3]  G. Drusano,et al.  Quantitative relationships between zidovudine exposure and efficacy and toxicity , 1994, Antimicrobial Agents and Chemotherapy.

[4]  S. Muramatsu,et al.  A sensitive nonisotopic method for the determination of intracellular azidothymidine 5'-mono-, 5'-di-, and 5'-triphosphate. , 1991, Analytical biochemistry.

[5]  W. Parks,et al.  The pharmacokinetics and safety of zidovudine in the third trimester of pregnancy for women infected with human immunodeficiency virus and their infants: Phase I acquired immunodeficiency syndrome clinical trials group study (protocol 082) , 1993 .

[6]  J. Falloon,et al.  The pharmacokinetics of zidovudine administered by continuous infusion in children. , 1989, Annals of internal medicine.

[7]  James H. Brown,et al.  A General Model for the Origin of Allometric Scaling Laws in Biology , 1997, Science.

[8]  Harold C. Standiford,et al.  Population pharmacokinetics of zidovudine , 1990 .

[9]  M. Green,et al.  3'-azido-3'-deoxythimidine (AZT) is glucuronidated by human UDP-glucuronosyltransferase 2B7 (UGT2B7). , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[10]  D. Schoenfeld,et al.  Zidovudine, didanosine, or both as the initial treatment for symptomatic HIV-infected children. AIDS Clinical Trials Group (ACTG) Study 152 Team. , 1997, The New England journal of medicine.

[11]  Nicholas H. G. Holford,et al.  A Size Standard for Pharmacokinetics , 1996, Clinical pharmacokinetics.

[12]  S. Broder,et al.  Plasma and cerebrospinal fluid pharmacokinetics of 3′‐azido‐3′‐deoxythymidine: A Novel pyrimidine analog with potential application for the treatment of patients with AIDS and related diseases , 1987, Clinical pharmacology and therapeutics.

[13]  R. Gelber,et al.  Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. , 1994, The New England journal of medicine.

[14]  S. Spector,et al.  Zidovudine Pharmacokinetics in Premature Infants Exposed to Human Immunodeficiency Virus , 1998, Antimicrobial Agents and Chemotherapy.

[15]  S. Pelton,et al.  Phase I evaluation of zidovudine administered to infants exposed at birth to the human immunodeficiency virus. , 1993, The Journal of pediatrics.

[16]  J. Falloon,et al.  Pharmacokinetics of zidovudine administered intravenously and orally in children with human immunodeficiency virus infection. , 1989, The Journal of pediatrics.

[17]  N. Beeching,et al.  Pharmacokinetics of zidovudine and dideoxyinosine alone and in combination in patients with the acquired immunodeficiency syndrome. , 1994, British journal of clinical pharmacology.

[18]  S. Spector,et al.  Virologic and immunologic response to nucleoside reverse-transcriptase inhibitor therapy among human immunodeficiency virus-infected infants and children. , 1999, The Journal of infectious diseases.

[19]  C. Gross,et al.  Concentration‐controlled zidovudine therapy , 1998, Clinical pharmacology and therapeutics.

[20]  P. Harrigan,et al.  Pharmacokinetics and antiretroviral activity of lamivudine alone or when coadministered with zidovudine in human immunodeficiency virus type 1-infected pregnant women and their offspring. , 1998, The Journal of infectious diseases.

[21]  S. Tadepalli,et al.  Radioimmunoassay for Retrovir, an anti-human immunodeficiency virus drug. , 1989, Journal of immunoassay.

[22]  P. de Miranda,et al.  Azidothymidine steady-state pharmacokinetics in patients with AIDS and AIDS-related complex. , 1989, The Journal of infectious diseases.