PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of aacPermissionsJournals.ASM.orgJournalAAC ArticleJournal InfoAuthorsReviewers
 
Antimicrob Agents Chemother. 1995 May; 39(5): 1101–1106.
PMCID: PMC162691

Pharmacokinetics of dapsone in human immunodeficiency virus-infected children.

Abstract

Dapsone, administered at various doses and schedules, has been proven to be a safe and effective alternative to trimethoprim-sulfamethoxazole for prevention of Pneumocystis carinii pneumonia (PCP) in adults with human immunodeficiency virus (HIV) infection. Dapsone is also recommended by the Centers for Disease Control for PCP prophylaxis in HIV-infected children. However, the suggested dosage regimen is based upon clinical experience with children with leprosy and dermatitis herpetiformis rather than pharmacokinetic and pharmacodynamic data obtained from the target patient population. In order to determine a rational dosage regimen that could be tested in clinical studies aimed at the evaluation of dapsone for the prevention of PCP in HIV-infected children, we studied the pharmacokinetics of dapsone following a 2-mg/kg of body weight oral dose in twelve HIV-positive children aged 9 months to 9 years. Plasma was collected at the following times after dapsone administration: 0, 2, 4, 6, 12, 24, 48, 72, and 96 h. The levels of dapsone in plasma were determined by high-performance liquid chromatography. Data were analyzed by noncompartmental methods. Expressed as means +/- standard deviations (ranges), the pharmacokinetic parameters were as follows: peak concentration in plasma, 1.12 +/- 0.48 (0.44 to 1.81) mg/liter; time to peak concentration in plasma, 3.8 +/- 1.3 (2 to 6) h; half-life at elimination phase, 24.2 +/- 7.1 (14.4 to 35.0) h; clearance from plasma divided by bioavailability (CL/F), 1.15 +/- 0.67 (0.37 to 2.63) ml/min/kg; and volume of distribution divided by bioavailability (V/F), 2.25 +/- 1.20 (1.00 to 4.57) liters/kg. Oral CL correlated negatively with age (r = 0.614 and P = 0.034), as did V (r = 0.631 and P = 0.028). As a consequence of the high interindividual variability in growth retardation, pharmacokinetic parameters correlated with measures of body development better than they did with age (e.g., for CL/F to height, r = 0.765 and P = 0.004, and for V/F to height, r = 0.748 and P = 0.005). Since oral CL from plasma and V were positively and highly correlated (r = 0.898 and P = 0.0001), a lower absolute F may be the cause, in part, of higher values for CL/F and V/F in smaller children. The results of this study warrant the testing of a 2-mg/kg dose of dapsone administered twice or thrice weekly to HIV-infected children. The monitoring of drug levels in plasma and dosage adjustment may be necessary for smaller children.

Full Text

The Full Text of this article is available as a PDF (208K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Antinori A, Murri R, Tamburrini E, De Luca A, Ortona L. Failure of low-dose dapsone-pyrimethamine in primary prophylaxis of Pneumocystis carinii pneumonia. Lancet. 1992 Sep 26;340(8822):788–788. [PubMed]
  • Blum RN, Miller LA, Gaggini LC, Cohn DL. Comparative trial of dapsone versus trimethoprim/sulfamethoxazole for primary prophylaxis of Pneumocystis carinii pneumonia. J Acquir Immune Defic Syndr. 1992;5(4):341–347. [PubMed]
  • Clotet B, Sirera G, Romeu J, Gimeno JM, Jou A, Condom MJ, Tor J, Foz M. Twice-weekly dapsone-pyrimethamine for preventing PCP and cerebral toxoplasmosis. AIDS. 1991 May;5(5):601–602. [PubMed]
  • Coker RJ, Nieman R, McBride M, Mitchell DM, Harris JR, Weber JN. Co-trimoxazole versus dapsone-pyrimethamine for prevention of Pneumocystis carinii pneumonia. Lancet. 1992 Oct 31;340(8827):1099–1099. [PubMed]
  • Crom WR, Relling MV, Christensen ML, Rivera GK, Evans WE. Age-related differences in hepatic drug clearance in children: studies with lorazepam and antipyrine. Clin Pharmacol Ther. 1991 Aug;50(2):132–140. [PubMed]
  • Falloon J, Lavelle J, Ogata-Arakaki D, Byrne A, Graziani A, Morgan A, Amantea MA, Ownby K, Polis M, Davey RT, Jr, et al. Pharmacokinetics and safety of weekly dapsone and dapsone plus pyrimethamine for prevention of pneumocystis pneumonia. Antimicrob Agents Chemother. 1994 Jul;38(7):1580–1587. [PMC free article] [PubMed]
  • May DG, Porter JA, Uetrecht JP, Wilkinson GR, Branch RA. The contribution of N-hydroxylation and acetylation to dapsone pharmacokinetics in normal subjects. Clin Pharmacol Ther. 1990 Dec;48(6):619–627. [PubMed]
  • May DG, Porter J, Wilkinson GR, Branch RA. Frequency distribution of dapsone N-hydroxylase, a putative probe for P4503A4 activity, in a white population. Clin Pharmacol Ther. 1994 May;55(5):492–500. [PubMed]
  • Girard PM, Landman R, Gaudebout C, Olivares R, Saimot AG, Jelazko P, Gaudebout C, Certain A, Boué F, Bouvet E, et al. Dapsone-pyrimethamine compared with aerosolized pentamidine as primary prophylaxis against Pneumocystis carinii pneumonia and toxoplasmosis in HIV infection. The PRIO Study Group. N Engl J Med. 1993 May 27;328(21):1514–1520. [PubMed]
  • Hughes WT, Kennedy W, Dugdale M, Land MA, Stein DS, Weems JJ, Jr, Palte S, Lancaster D, Gidan-Kovnar S, Morrison RE. Prevention of Pneumocystis carinii pneumonitis in AIDS patients with weekly dapsone. Lancet. 1990 Oct 27;336(8722):1066–1066. [PubMed]
  • Kemper CA, Tucker RM, Lang OS, Kessinger JM, Greene SI, Deresinski SC, Stevens DA. Low-dose dapsone prophylaxis of Pneumocystis carinii pneumonia in AIDS and AIDS-related complex. AIDS. 1990 Nov;4(11):1145–1148. [PubMed]
  • Lake-Bakaar G, Tom W, Lake-Bakaar D, Gupta N, Beidas S, Elsakr M, Straus E. Gastropathy and ketoconazole malabsorption in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med. 1988 Sep 15;109(6):471–473. [PubMed]
  • Mallolas J, Zamora L, Gatell JM, Miró JM, Vernet E, Valls ME, Soriano E, SanMiguel JG. Primary prophylaxis for Pneumocystis carinii pneumonia: a randomized trial comparing cotrimoxazole, aerosolized pentamidine and dapsone plus pyrimethamine. AIDS. 1993 Jan;7(1):59–64. [PubMed]
  • Martin MA, Cox PH, Beck K, Styer CM, Beall GN. A comparison of the effectiveness of three regimens in the prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients. Arch Intern Med. 1992 Mar;152(3):523–528. [PubMed]
  • Metroka CE, McMechan MF, Andrada R, Laubenstein LJ, Jacobus DP. Failure of prophylaxis with dapsone in patients taking dideoxyinosine. N Engl J Med. 1991 Sep 5;325(10):737–737. [PubMed]
  • Mirochnick M, Michaels M, Clarke D, Breña A, Regan AM, Pelton S. Pharmacokinetics of dapsone in children. J Pediatr. 1993 May;122(5 Pt 1):806–809. [PubMed]
  • Morselli PL, Franco-Morselli R, Bossi L. Clinical pharmacokinetics in newborns and infants. Age-related differences and therapeutic implications. Clin Pharmacokinet. 1980 Nov-Dec;5(6):485–527. [PubMed]
  • Opravil M, Joos B, Lüthy R. Levels of dapsone and pyrimethamine in serum during once-weekly dosing for prophylaxis of Pneumocystis carinii pneumonia and toxoplasmic encephalitis. Antimicrob Agents Chemother. 1994 May;38(5):1197–1199. [PMC free article] [PubMed]
  • Philip PA, Roberts MS, Rogers HJ. A rapid method for determination of acetylation phenotype using dapsone. Br J Clin Pharmacol. 1984 Apr;17(4):465–469. [PMC free article] [PubMed]
  • Podzamczer D, Santín M, Jimenez J, Casanova A, Bolao F, Gudiol GR. Thrice-weekly cotrimoxazole is better than weekly dapsone-pyrimethamine for the primary prevention of Pneumocystis carinii pneumonia in HIV-infected patients. AIDS. 1993 Apr;7(4):501–506. [PubMed]
  • Slavin MA, Hoy JF, Stewart K, Pettinger MB, Lucas CR, Kent SJ. Oral dapsone versus nebulized pentamidine for Pneumocystis carinii pneumonia prophylaxis: an open randomized prospective trial to assess efficacy and haematological toxicity. AIDS. 1992 Oct;6(10):1169–1174. [PubMed]
  • Stavola JJ, Noel GJ. Efficacy and safety of dapsone prophylaxis against Pneumocystis carinii pneumonia in human immunodeficiency virus-infected children. Pediatr Infect Dis J. 1993 Aug;12(8):644–647. [PubMed]
  • Torres RA, Barr M, Thorn M, Gregory G, Kiely S, Chanin E, Carlo C, Martin M, Thornton J. Randomized trial of dapsone and aerosolized pentamidine for the prophylaxis of Pneumocystis carinii pneumonia and toxoplasmic encephalitis. Am J Med. 1993 Dec;95(6):573–583. [PubMed]
  • Zuidema J, Hilbers-Modderman ES, Merkus FW. Clinical pharmacokinetics of dapsone. Clin Pharmacokinet. 1986 Jul-Aug;11(4):299–315. [PubMed]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)