Pharmacologic Characteristics of Indinavir, Didanosine, and Stavudine in Human Immunodeficiency Virus-Infected Children Receiving Combination Therapy

Abstract

The use of human immunodeficiency virus (HIV) protease inhibitors in children has lagged behind that in adults because of the lack of suitable pediatric formulations and information on safe and effective dosing regimens. This study was designed to obtain pharmacokinetic information on indinavir, administered to HIV-infected children also receiving therapy with two nucleoside agents, and to explore relationships between pharmacokinetic parameters and anti-HIV effect. Indinavir was initiated at a dose of 500 mg/m 2 every 8 h. Plasma indinavir concentrations were measured every 4 weeks; the dose or dosing interval was adjusted to maintain trough concentrations of >0.1 mg/liter. All children were evaluated clinically at baseline and every 4 weeks.

Pharmacokinetics of Stavudine and Didanosine Coadministered with Nelfinavir in Human Immunodeficiency Virus-Exposed Neonates

“…In conjunction with the short half-lives, these data suggest that for both drugs the steady-state conditions are reached in infants by day 14 of administration. Previous studies showed that the mean AUC values for d4T after administration of a dose of 1 mg/kg twice daily in children were 1,629 to 2,509 ng ⅐ h/ml (8,12,13), which are comparable to the values obtained in the present study (1,866 and 1,603 ng ⅐ h/ml). The C max values obtained for d4T in the present study (463 and 507 ng/ml) are in proximity to the C max values of 510 to 1,099 ng/ml obtained in previous studies (8,12).…”

“…Previous studies showed that the mean AUC values for d4T after administration of a dose of 1 mg/kg twice daily in children were 1,629 to 2,509 ng ⅐ h/ml (8,12,13), which are comparable to the values obtained in the present study (1,866 and 1,603 ng ⅐ h/ml). The C max values obtained for d4T in the present study (463 and 507 ng/ml) are in proximity to the C max values of 510 to 1,099 ng/ml obtained in previous studies (8,12). Furthermore, the half-lives in the present study (1.8 and 1.4 h) are similar to those reported in previous studies (1.1 to 1.4 h) (8,12,13).…”

Indinavir alters regulators of protein anabolism and catabolism in skeletal muscle

“…A comparable dosing regimen impairs insulinstimulated glucose uptake in muscle (23). At the conclusion of the 4-h protocol, this infusion protocol produced a plasma indinavir concentration modestly higher than peak levels seen in human subjects taking the drug orally (15).…”

“…The plasma concentrations of TNF-␣ and IL-6 were measured using a solid-phase sandwich enzyme-linked immunosorbent assay (BioSource International, Cama-rillo, CA). The plasma concentration of indinavir was measured by reverse-phase HPLC (15).…”

Development of a Population Simulation Model for HIV Monotherapy Virological Outcomes Using Lamivudine

“…These nucleotide analogues reversibly compete with the natural dNTP for the HIV-1 reverse transcriptase (RT) for incorporation into the elongating proviral DNA early in the viral replication cycle, during which the viral RNA genome is reverse transcribed into DNA, a process necessary for continued viral replication (Sommadossi, 1998). Unlike NNRTI and PI, in which the antiviral agents' pharmacodynamics are directly predicted by the dose trough plasma concentrations (C min ; Acosta et al, 1999;Fletcher, 1999;Fletcher et al, 2000;Lorenzi et al, 1997;Stein et al, 1996), the efficacy of NRTI may be more related to peak plasma concentrations (C max ), which would drive cellular accumulation and phosphorylation of the NRTI to the long-lived nucleoside triphosphate, unless phosphorylation is saturated at clinically relevant concentrations, as is the case for zidovudine (Barry et al, 1996).…”