Pharmacokinetics, safety and efficacy of lopinavir/ritonavir in infants less than 6 months of age: 24 week results

Chadwick, Ellen G.; Capparelli, Edmund V.; Yogev, Ram; Pinto, Jorge; Robbins, Brian L.; Rodman, John H.; Chen, Jie; Palumbo, Paul; Serchuck, Leslie; Smith, Elizabeth; Hughes, Michael L.

doi:10.1097/qad.0b013e3282f2be1d

Cited by 73 publications

(78 citation statements)

References 9 publications

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“…However, the physiological circumstances in very young infants and neonates probably alter the relationship between body weight and clearance and volume of distribution, explaining the moderate decrease of clearance BSV. The variabilities, BSV and residual, remained at high levels, as previously observed in other childhood studies [1,2,4]. In adults, the residual variability, approximated to 0.21 [from the additive 1.15 mg l -1 and proportional 0.075 components reported, 0.21 = square root ((1.15/ 6) 2 + 0.075 2 ] was lower and BSVs were estimated via a full variance-covariance matrix, explaining in part a lower BSV(CL) value, 0.17 [3].…”

Section: Discussionsupporting

confidence: 86%

“…Although the PMA effect on F decreased marginally the BSVs and significantly the AIC and BIC criteria, the final CL/F70 and V/F70 values extrapolated to a 70 kg adult with F = 1 are similar to the adult estimates, 5.73 l h -1 and 61.6 l, respectively [3], whicht supports this population pharmacokinetic model. Higher apparent CL and V values in the youngest infants of a group have also been observed in other LPV/r childhood studies [1,2].…”

Section: Discussionsupporting

confidence: 80%

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Lopinavir/ritonavir population pharmacokinetics in neonates and infants

Urien

Firtion

Anderson

et al. 2011

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Lopinavir/ritonavir pharmacokinetics have been fully investigated in adults and children. WHAT THIS STUDY ADDS• Lopinavir/ritonavir population pharmacokinetics in 96 neonates and infants from birth to less than 2 years (1.16 to 10.4 kg) showed that CL/F and V/F were dependent on body weight on an allometric basis and post-menstrual age. AIMSBecause of immature hepatic metabolism, lopinavir could present specific pharmacokinetics in the first weeks of life. We aimed at determining the optimal dosing regimen in neonates and infants weighing 1 to 10.5 kg. METHODSLopinavir/ritonavir (LPV/r) pharmacokinetics were studied in 96 infants using a population approach. RESULTSA one-compartment model described LPV/r pharmacokinetics. Normalized to a 70 kg adult using allometry, clearance (CL/F) and distribution volume (V/F) estimates were 5.87 l h -1 70 kg -1 and 91.7 l 70 kg -1. The relative bioavailabilty, F, increased with post-menstrual age (PMA) and reached 50% of the adult value at 39.7 weeks. CONCLUSIONSSize and PMA explained some CL/F and V/F variability in neonates/infants. Based upon trough concentration limitations, suggested LPV/r dosing regimens were 40 mg 12 h -1 , 80 mg 12 h -1 and 120 mg 12 h -1 in the 1-2 kg, 2-6 kg and 6-10 kg group, respectively.British Journal of Clinical Pharmacology DOI:10.1111DOI:10. /j.1365DOI:10. -2125DOI:10. .2011 956 / Br J Clin Pharmacol / 71:6 / 956-960

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Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 80%

Lopinavir/ritonavir population pharmacokinetics in neonates and infants

Urien

Firtion

Anderson

et al. 2011

Brit J Clinical Pharma

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“…Very young children (< 6-months) require increased doses/BSA of lopinavir/ritonavir in order to achieve the same lopinavir concentrations as those in older children and adults [28, 36,31], and a 39% increase in CL/F has been reported for boys compared to girls in children older than 12 years [37].…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics of lopinavir in combination with rifampicin-based antitubercular treatment in HIV-infected South African children

Elsherbiny

Ren

McIlleron

et al. 2010

Eur J Clin Pharmacol

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“…Ritonavir was previously used as an antiretroviral PI. Ritonavir increases the bioavailability of other PIs (mainly lopinavir or darunavir in children) via effects on P450 cytochrome and is now used in low doses to achieve this effect [7,8]. Although generally very well tolerated in children and adolescents, r-PI adversely affected growth in infants in a randomized study, despite better antiviral efficacy compared to the control group [9].…”

Section: Introductionmentioning

confidence: 99%

Adrenal Enzyme Impairment in Neonates and Adolescents Treated with Ritonavir and Protease Inhibitors for HIV Exposure or Infection

Kariyawasam

Simon

Laborde³

et al. 2014

Horm Res Paediatr

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Background: Human deficiency virus (HIV) protease inhibitors (PIs) are widely used drugs whose effects are pharmacologically enhanced by ritonavir, a potent cytochrome P450 inhibitor. We reported previously that prophylactic postnatal ritonavir-PI therapy in HIV-exposed neonates was associated with increases in plasma 17-hydroxyprogesterone (17-OHP) and dehydroepiandrosterone sulfate (DHEA-S). Aims: To further investigate adrenal function in neonates and adolescents given ritonavir-PI. Methods: Adrenal function was assessed prospectively in 3 HIV-exposed neonates given short-term prophylactic treatment and 3 HIV-infected adolescents given long-term treatment. Plasma cortisol, 17-OHP, 17-OH-pregnenolone, DHEA-S, and androstenedione were measured before and after ACTH administration. Results: None of the patients had clinical signs of adrenal dysfunction. The only neonate exposed to ritonavir-PI in utero had up to 3-fold increases in plasma 17-OHP. Increases in 17-OH-pregnenolone of up to 3.1-fold were noted in 4 of the 6 patients, and all 6 patients had elevations in DHEA-S (up to 20.4-fold increase) and/or DHEA (up to 4.7-fold) and/or androstenedione (up to 5.2-fold). All these parameters improved after treatment completion. Conclusion: Neonates and adolescents given ritonavir-PI exhibit a similar adrenal dysfunction profile consistent with an impact on multiple adrenal enzymes. These abnormalities require evaluation, given the potentially long exposure times.

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Pharmacokinetics, safety and efficacy of lopinavir/ritonavir in infants less than 6 months of age: 24 week results

Abstract: Despite higher clearance in infants 6 weeks to 6 months of age, a twice daily dose of 300/75 mg/m LPV/r provided similar exposure to that in older children, was well tolerated and provided favorable virological and clinical efficacy.

Cited by 73 publications

References 9 publications

Lopinavir/ritonavir population pharmacokinetics in neonates and infants

Lopinavir/ritonavir population pharmacokinetics in neonates and infants

Population pharmacokinetics of lopinavir in combination with rifampicin-based antitubercular treatment in HIV-infected South African children

Adrenal Enzyme Impairment in Neonates and Adolescents Treated with Ritonavir and Protease Inhibitors for HIV Exposure or Infection

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