3 PK in Paediatric Populations Developmental changes can significantly affect ADMEMajority of PK data in paediatric patients obtained in older childrenSubstantial intra and inter patient variability
4 Issues for dosing of ART in children Large variability in pharmacokinetic (PK) parametersage (and PK data by age-group often sparse)effect of nutritional statusethnicityMethods of dose calculation (per m2 or per kg)Ability to give with/without food (ddI, NFV)High within and between individual variability and PKAge a very important facros – high doses required in infants in particular for most drugs esp PI and NNRTIsBioequivalence varies by formulationi – eg efv need to give higher dose of lquid
5 Impact of Nutrition on PK (Can have a profound effect) Diminished protein status in malnourished children results in lower plasma proteinsIncreasing concentrations of ‘free’ drugSeverely malnourished children have decreased CYP450 metabolismReduced hepatic clearanceSeverely malnourished children have decreased GFRReduced renal clearanceMurry et al Int J Cancer 1998; 11: Jorquera F et al Nutrition 1996; 12:
6 Same dose but different plasma concentrations Mechanism of Genetic Variability in Drug ResponseSame dose but different plasma concentrationsDrugAAUC 110ConcentrationGCCCCGCCTCP 4501wild typeTimeDrugBAUC 2010GCCCCACCTCConcentrationP4501mutationTimeME3012.PPT
7 A Common CYP2B6 Variant Associated with EFV PK and CNS Side Effects Slide #7A Common CYP2B6 Variant Associated with EFV PK and CNS Side EffectsA CYP2B6 polymorphism.More common in African-Americans than European-Americans.Associated with higher EFV levels, and increased CNS AE’s.Additional studies needed.
8 Left Hand Y Axis EFV concentration on a log scale Resistance WT at wk 6Left Hand Y Axis EFV concentration on a log scaleOrientation slide, blue points EFV concSecond right hand y axis plasma viral load log scale represented by green tianglesviral load over timeVertical arrows 1,2 and 3 weeksLower Horizontal red lines protein corrected EC95 for EFV 92Upper red line lower end of therapeutic rangeHorizontal bar drugs patient continued to take0 patient stopped EFVS. Taylor et al. 11th CROI Abs 131
9 Finally T1/2 > 200 hours although LFTs not deranged This is the 3rd African woman with therapeutic levels at week 2 +/- week 3Intersetingly she also developed toxicty with NVP data on nvp levels to be addedViral load and NVP data needs addingS. Taylor et al. 11th CROI Abs 131
10 Note: Difference between plasma and intracellular half life Time (hours)5101520251100100010000IntracellularCarbovir-TPt1/ hPlasma Abacavirt1/ hIntracellular CBV-TP,fmol/million cellPlasma Abacavir,ng/mLPiliero P, et al. 43rd ICAAC 2003, Abstr. A-1797
11 NRTI (intracellular) and NNRTI half lives ZDVTP 7 h NVP hd4TTP 7 h EFV 35 h3TCTP 16 hCBVTP 20 hddATP 25 hTDFDP 60 hFTCTP 39 h
12 Balancing drugs with different half lives Last DoseDay 1Day 2MONOTHERAPYDrug concentrationKey PointsConsiderations of forgiveness are critical for ensuring “coverage” if a dose is missedIC90Zone of potential replicationIC5012243648Time (hours)S. Taylor et al. 11th CROI Abs 131
13 3TC Clearance in Children Sokol E, et al. AAC 2000, 44:590-97
14 NVP Concentrations in Children by Age < 2 years2-8 years> 8 years250050007500100001250015000175002000022500NVP Concentration (ng/ml)
17 Nelfinavir PK in Children Children <2 y at risk of subtherapeutic NFV levelsBergshoeff et al, 2002
18 Nelfinavir Troughs with TID and BID Dosing NFV PK were evaluated in 35 children (8.1 ± 3.5 yrs) receiving mg/kg q8h or 50 mg/kg q12 h with food.Trough values were:1.55 mg/L ( mg/L) for TID dosing1.11 mg/L (nd-6.08 mg/L) with BID.1/11 (9%) in TID group vs. 7/14 (50%) in BID group had values < 1 mg/L (p=0.042).* Gatti G, et al. Clin Infect Dis, 2003;36:
19 Nelfinavir Use in Children The proportion of children 2-13 years of age achieving an HIV RNA level < 400 cpm through 48 wks ranged from 26-42%.Response rates in children < 2 years of age appeared to be poorer than those ≥ 2 years.Highly variable exposure remains a significant problem in the use of nelfinavir in pediatric patients.Viracept Package Insert, March 29, 2004
20 LPV Concentrations in Children by Age 500004000030000LPV Concentration (ng/ml)2000010000< 2 years2-8 years> 8 years
22 Reduced Lopinavir Plasma Concentrations in Pregnancy 109876Median (± SE) Lopinavir (μg/mL)5432Protein-adjusted IC50 for LPV1One of the more important issues that has emerged in pharmacology relates to the use of antiretroviral drugs in pregnancy. Previous data had suggested that pregnancy—particularly in the third trimester—might be associated with lower protease inhibitor exposures, although not necessarily to a clinically significant degree. The Pediatric ACTG examined boosted lopinavir in a cohort of patients between 30 and 36 weeks of pregnancy, and also examined the same patients 6 to 12 weeks after delivery. The study was designed to compare the drug exposures in these women to the expected levels derived from nonpregnant women. As shown in the slide, during pregnancy (shown in orange) the concentrations of lopinavir were markedly lower than one would expect in a nonpregnant woman. Postpartum, the lopinavir concentrations rose, but not to the levels that one would anticipate in nonpregnant women. The implications of these findings are unclear. The majority of women in this study maintained virologic suppression while receiving lopinavir/ritonavir with 2 NRTIs. However, the reduction in plasma concentrations is a concern, and has led the Pediatric ACTG to amend this study to examine higher doses of boosted lopinavir during the third trimester of pregnancy to see if one can consistently achieve acceptable drug levels. Another study at the meeting evaluated nevirapine and showed that concentrations of nevirapine were reduced in pregnancy compared with nonpregnant women, but in that study, the degree of reduction was unlikely to be clinically relevant.For more information, please go online to:12345678910111213Time Post Dose (hours)Pregnancy (n = 17)Postpartum (n = 8)Nonpregnant historical controlsNote also abstract 4644 – NVP plasma exposure reduced in pregnant vs nonpregnant womenStek et al. Abstract LBOrB08.
23 Key Points Incomplete knowledge of pharmacology Marked Inter individual variabilityNutritional status & PKAge group & PKEthnicity & PKDosing according to weight or BSA seems arbitary.Equivalence – Pharmaceutic & BioequivalenceBd vs qdThe future of PIs in children1st line to ?????