Summary
The variability of the pharmacokinetics of zidovudine after its oral administration to 36 AIDS patients has been investigated by measuring the plasma and urine levels of zidovudine and its metabolite on Days 1 and 35 of continuous treatment. A two-phase absorption model was first defined from well-documented data in 12 subjects. The population characteristics of the kinetic parameters for both days were estimated by a nonparametric method.
On Day 1, the mean (coefficient of variation) volume of distribution of zidovudine was 94.41 (90%), its mean half-life was 0.81 h (107%) and its mean oral clearance was 117l·h−1 (57%) and on Day 35, these values were, respectively, 1121 (139%), 0.75 h (181%) and 295l·h−1 (196%). The results confirm the large interindividual and intraindividual variation in zidovudine kinetics. The four covariates included in the population analysis (body weight, serum haemoglobin, creatinine and bilirubin) did not show clear relationship to the kinetic parameters.
Thirty-four subjects were follow-up clinically for 99 days to 367 days after initiation of zidovudine therapy. The relationship between individual kinetic parameters (determined by Bayesian estimation), mean concentration profiles and outcome was studied through survival analysis. Long-term efficacy was defined as the prevention of opportunistic infections, which occurred in 13 patients. No clinical or kinetic variables, nor the individual zidovudine concentration profiles were found to predict the occurrence of an opportunistic infection. Toxicity was defined as a 20%-decrease in serum haemoglobin, which occurred in 13 patients. A significant relationship between mean daily concentration and toxicity was found, with an hazard of occurrence of toxicity 4.3-times larger when the mean steady stade concentration was 0.8 mg·l−1 than 0.6. The results indicate that zidovudine dosage should be individualised.
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References
Akaike H (1974) A new look at the statistical model identification. IEE Trans Automat Contr 19: 716–723
Balis FM, Pizzo PA, Murphy RF, Eddy J, Jarosinski PF, Falloon J, Broder S, Poplack DG (1989) The pharmacokinetics of zidovudine administered by continuous infusion in children. Ann Intern Med 110: 279–285
Bard Y (1974) Nonlinear parameter estimation. Academic Press, New York
Beal SL, Sheiner LB (1980) The NONMEM system. Am Statist 34: 118–119
Collier AC, Bozzette S, Coombs RW, Causey DM, Schoenfeld DA, Stephen A, Spector MD, Pettinelli CB, Davies G, Richman DD, Leedom JM, Kidd P, Corey L (1990) A pilot study of low-dose zidovudine in human immunodeficiency virus infection. N Engl J Med 323: 1015–1021
Collins JM, Unadkat JD (1989) Clinical pharmacokinetic of zidovudine: an overview of current data. Clin Pharmacokinet 17: 1–9
Cox DR (1972) Regression models and life-tables (with discussion). J R Stat Soc [B] 34: 187–220
Creagh-Kirk T, Doi P, Andrews E, Nusinoff-Lehrman S, Tilson H, Hoth D, Barry DW (1988) Survival experience among patients with AIDS receiving zidovudine: follow-up of patients in a compassionate plea program. JAMA 260: 3009–3015
Deray G, Diquet B, Martinez F, Vidal AM, Ben Himda M (1988) Pharmacokinetics of zidovudine in a patient with maintenance hemodialysis. N Engl J Med 319: 1606–1607
Diquet B, Simon F, Ory-Lavollée L, Brun-Vezinet F, Colin JN, Vigie Group (1989) Pharmacokinetics of zidovudine and p24 Ag time course in 48 ARC patients under steady-state conditions. Proceedings of the Fifth International Conference on AIDS. Montréal, June 4–9 1989, pp. 279
Drusano GL, Geoffrey JY, Lambert JS, Seidlin M, Dolin R, Valentine FT (1992) Relationship between dideoxyinosine exposure, CD4 counts, and p24 antigen levels in human immunodeficiency virus infection. A phase I trial. Ann Intern Med 116: 562–566
Escolano S, Mentré F, Golmard JL, Diquet B, Mallet A (1991) A reduced dose of zidovudine in patients with AIDS (letter). N Engl J Med 324: 995. Correction 326: 1571
Fischl MA, Parker CB, Pettinelli C, Wulfsohn M, Hirsch MS, Collier AC, Antoniskis D, Ho M, Richman DD, Fuchs E, Merigan TC, Reichman RC, Gold J, Steigbigel N, Leoung GS, Tasheed S, Tsiatis A, AIDS Clinical Trials Group (1990) A randomized controlled trial of a reduced daily dose of zidovudine in patients with the acquired immunodeficiency syndrome. N Engl J Med 323: 1009–1014
Fischl MA, Richman DD, Grieco MH, Gottlieb MS, Volberding PA, Laskin OL, Leedom JL, Groopman JE, Mildvan D, Schooley RT, Jackson GG, Durack DT, King D, AZT Collaborative Working Group (1987) The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. N Engl J Med 317: 185–191
Gibaldi M, Perrier D (1982) Pharmacokinetics, 2nd edn. Dekker, New York
Gitterman SR, Drusano GL, Egorin MJ, Standiford GC, Geterans Administration Cooperative Studies Group (1990) Population pharmacokinetics of zidovudine. Clin Pharmacol Ther 48: 161–167
Good SS, Reynolds DJ, de Miranda P (1988) Simultaneous quantification of zidovudine and its glucuronide in serum by high-performance liquid chromatography. J Chromatogr 431: 123–133
Hamilton JD, Hartigan PM, Simberkoff MS, Day PL, Diamond GR, Dickinson GM, Drusano GL, Egorin MJ, George WL, Gordin FM, Hawkes CA, Jensen PC, Klimas NG, Labriola AM, Lahart CJ, O'Brien WA, Oster CN, Weinhold KJ, Wray NP, Zolla-Pazner SB, the Veterans Affairs Cooperative Study Group on AIDS Treatment (1992) A controlled trial of early versus late treatment with zidovudine in symptomatic human immunodeficiency virus infection. N Engl J Med 326: 437–443
Jacobson MA, Bacchetti P, Kolokathis A, Chaisson RE, Szabo Susan, Polsky B, Vamainis GT, Mildvan D, Abrams D, Wilber J, Winger E, Sacks HS, Hendricksen C, Moss A (1991) Surrogate markers for survival in patients with AIDS and AIDS related complex treated with zidovudine. Br Med J 302: 73–78
Kalbfleisch JD, Prentice RL (1980) The statistical analysis of failure time data, Wiley, New York
Kaplan RL, Meier P (1958) Nonparametric estimation form incomplete observations. J Am Stat Assoc 53: 457–481
Kornhauser DM, Hendrix CW, Nerhood LJ, Petty BG, Woods AS, Bartlett JG, Lietman PS (1989) Probenecid and zidovudine metabolism. Lancet II: 473–475
Landaw EM, Distefano JJ (1984) Multiexponential, multicompartmental and noncompartmental modeling. II. Data analysis and statistical considerations. Am J Physiol 246: 665–677
Langtry HD, Campoli-Richards DM (1989) Zidovudine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs 37: 408–450
Lotterer E, Ruhnke M, Trautman M, Beyer R, Bauer FE (1991) Decreased and variable systemic availability of zidovudine in patients with AIDS if administered with a meal. Eur J Clin Pharmacol 40: 305–308
Mallet A (1986) A maximum likelihood estimation method for random coefficient regression models. Biometrika 73: 645–656
Mallet A, Mentré F, Gilles J, Kelman AW, Thomson AN, Bryson SM, Whiting B (1988) Handling covariates in population pharmacokinetics with an application to gentamicin. Biomed Meas Inform Contr 2: 673–683
Mentré F, Mallet A, Diquet B, Turk P, Colin JN, Dowd P (1989) Population kinetics of AZT in AIDS patients. Eur J Clin Pharmacol 36: 230
Mentré F, Mallet A (1991) Relationships between intra or interindividual variability and biological covariates: application to zidovudine pharmacokinetics. In: D'Argenio (ed) Advanced methods of pharmacokinetic and pharmacodynamic systems analysis. Plenum Press, New York, pp. 119–128
Mentré F, Mallet A (1994) Handling covariates in population pharmacokinetics. Int J Bio-Med Comput (in press)
Merigan TC (1991) Treatments of AIDS with combinations of anti-retroviral agents. Am J Med 90 [Suppl 4A]: 8–17
Miranda P de, Good SS, Yarchoan R, Thomas RV, Blum MR, Myers CE, Broder S (1989) Alteration of zidovudine pharmacokinetics by probenecid in patients with AIDS or AIDS-related complex. Clin Pharmacol Ther 46: 731–739
Nordic Medical Research Councils' HIV Therapy Group (1992) Double blind dose-response study of zidovudine in AIDS and advanced HIV infection. Br Med J 304: 13–17
Richman DD, Fischl MA, Grieco MH, Gottlieb MS, Volberding PA, Laskin LO, Leedom JM, Groopman JE, Mildvan D, Hirsch MS, Jackson GG, Durack DT, Nusinoff-Lehrman S, AZT Collaborative Working Group (1987) The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. N Engl J Med 317: 192–197
Stagg MP, Cretton EM, Kidd L, Diasio RB, Sommadossi JP (1992) Clinical pharmacokinetics of 3′-azido-deoxythymidine (zidovudine) and catabolites with formation of a toxic catabolite, 3′-amino-3′-doxythymidine. Clin Pharmacol Ther 51: 668–676
Sheiner LB (1990) Implications of an alternative approach to doseresponse trials. J AIDS 3 [Suppl 2]: 20–26
Sheiner LB (1991) The intellectual health of clinical drug evaluation. Clin Pharmacol Ther 50: 4–9
Singlas E, Pioger JC, Taburet AM, Colin JN, Fillastre JP (1989) Zidovudine disposition in patients with severe renal impairment: influence of hemodialysis. Clin Pharmacol Ther 46: 190–197
Steimer JL, Mallet A, Mentré F (1985) Estimating interindividual pharmacokinetic variability. In: Rowland M, Sheiner LB, Steimer JL (eds) Variability in drug therapy. Raven Press, New York, pp. 65–111
Steinberg JP, Spear JB, Murphy RL, Wallemark CB, Benson CA, Kessler HA, Pottage JC, Phair JP (1989) Predictors of outcome in AIDS patients receiving zidovudine. J AIDS 2: 229–234
Taburet AM, Naveau S, Zorga G, Colin JN, Delfraissy JF, Chaput JC, Singlas E (1990) Pharmacokinetics of zidovudine in patients with liver cirrhosis. Clin Pharmacol Ther 6: 731–739
Thomson AH, Whiting B (1992) Bayesian parameter estimation and population pharmacokinetics. Clin Pharmacokinet 22: 447–467
Unadkat JD, Tartagliona T, Opheim K, Collier A, Cummings D, Corey L (1988) Estimation of population pharmacokinetic parameters of zidovudine (ZDV or AZT) from AIDS patients enrolled in phase II/III trial. Proceedings of Fourth International Conference on AIDS, vol. 2. Stockholm, June 12–16, pp. 176
Verotta D, Sheiner LB (1988) Parametric and semi-parametric approaches to non-steady-state pharmacokinetic and pharmacodynamic data. Biomed Meas Inform Contr 2: 161–169
Vilain J, Francheteau P, Steimer JL (1988) PHACIN, un logiciel pour la modélisation compartimentale et l'estimation des paramètres pharmacocinétiques. In: Grémy F (ed) Journées d'Informatique Médicale de Montpellier. Sauramps Medical, Montpellier, pp. 124–132
Volberding PA, Lagakos SW, Koch MA, Pettinelli C, Myers MW, Booth DK, Balfour HH, Reichman RC, Bartlett JA, Hirsch MS, Murphy RL, Hardy WD, Soeiro R, Fischl MA, Bartlett JG, Merigan TC, Hyslop NE, Richman DD, Valentine FT, Corey L, AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases (1990) Zivovudine in asymptomatic human immunodeficiency virus infection. N Engl J Med 322: 941–949
Yarchoan R, Weinhold KJ, Lyerly HK, Gelman E, Blum RM, Shearer GM, Mitsuya H, Collins JM, Myers CE, Klecker RW, Markham PD, Durack DT, Nusinoff Lehrman S, Barry DW, Fischl MA, Gallo RC, Bolognesi DP, Broder S. (1986) Administration of 3′-azido-3′-deoxythymidine, an inhibitor of HTLV-III/LAV replication, to patients with AIDS or AIDS-related complex. Lancet I: 570–580
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Mentré, F., Escolano, S., Diquet, B. et al. Clinical pharmacokinetics of zidovudine: inter and intraindividual variability and relationship to long term efficacy and toxicity. Eur J Clin Pharmacol 45, 397–407 (1993). https://doi.org/10.1007/BF00315509
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DOI: https://doi.org/10.1007/BF00315509