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Helen McIlleronDivision of Clinical PharmacologyUniversity of Cape Town
7TH FIDSSA 2017
Treatment of HIV/TB co-infection in children; drug-drug interactions
CYP3A4
inhibition of enzymes/transporters
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4
SUBSTRATE/ INHIBITOR
o concentration
o binding affinity
o enzyme turnover
induction of enzymes/transporters
Tompkins and Wallace (2007)
• Rifampicin (RIF) causes drug-drug interactions by:– Inducing many cytochrome (CYP) p450’s
– Also increased:p-glycoprotein
multiple drug resistance protein 2
organic-anion transporting polypeptide
UDP-glucuronyl- & sulfotransferase
Berger B, Front Pharmacol. 2016 Nov 21;7:443.
Complex and compounded interactions
CYP3A4
CYP3A4
CYP3A4
P-gp
P-gp
P-gp
P-gp
P-gp
P-gp
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4CYP3A4
CYP3A4
Like many PIs, lopinavir is a dual substrate of
CYP3A4 and p-glycoprotein
LPV
LPV/r
CYP3A4
P-gp
P-gp
P-gp
P-gp
P-gp
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4CYP3A4
CYP3A4
CYP3A4
CYP3A4
P-gp
lopinavir
CYP3A4
CYP3A4
CYP3A4
P-gp
P-gp
P-gp
P-gp
P-gp
P-gp
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4CYP3A4
CYP3A4
P-gp
P-gp
P-gp
P-gp
P-gp
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4
P-gp
P-gp
P-gp
P-gp
P-gp
P-gp
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4
P-gp
P-gp
P-gp
P-gp
P-gp
P-gp
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4
CYP3A4
P-gp
CYP3A4
CYP3A4
CYP3A4
CYP3A4CYP3A4
LPV/r+
rifampicin
Superboosted LPV during TB treatment Std LPV/r after TB treatment
(Kaletra® oral solution+extra ritonavir)
Rabie et al. CROI 2017
Superboosted lopinavir for under 3-year olds on 1st-line ART & TB treatment
McIlleron et al., Antivir Ther. 2011;16(3):417-21..
Ritonavir is not available in many settings
12 hourly doubled doses of LPV/r
Cmin, mg/L ↓83%
Cmin <1 mg/L 60%
worse VL outcomes than superboosting
concerns it contributes to development of resistance
Weight
(kg)
model predicted 8
hourly LPV dose in
LPV/r (mg/kg)
3-5.9 27
6-9.9 21
10-13.9 20
14-19.9 18
Zhang et al. Antiviral Therapy 2012;17(1):25-33. .
Doubled doses of LPV/r
PK in children dosed using model-predicted 8-hourly
doses of LPV/r
Seeking feasible doses/formulations for young children with TB/HIV:-
Williamson et al., AAC 2013; 57: 6366–69
• Higher in vitro rifampicin exposures increased metabolizing enzyme and transporter expression.
Will revised RIF (and INH) doses alter the drug-drug interactions between ART and TB treatment?
rifabutinwith LPV/r
Moultrie et al., JAC 2015
5 mg/kg rifabutin 3 x/week in children < 5 years.
efavirenz PK in children
Bienczak, et al., Br J Clin Pharmacol 2016; 82(1):185-98
CYP 2B6
CYP 2A6
PG
Luetkemeyer et al., CID 2015;60:1860–3
drug-drug-drug-genetic interaction!
McI
llero
n e
t a
l., A
IDS.
20
13
;27
:19
33
-40
.
impact of TB treatment on efavirenz PK in childrenin children
RH preventive therapy reduces trough NVP concentrations by 33% in infants on TB preventive
therapy – use ITP
median 1.66 (IQR 1.32, 2.37) mg/L vs. 2.11 (IQR 1.48, 3.27) mg/L early in treatment. median 0.89 (0.60, 1.57) mg/L vs. 1.39 (IQR 1.01, 1.98) mg/L later in treatment.
raltegravir + rifampicin in adult HNVs
dolutegravir + rifampicin in HNVs
absorption is saturable.→ 12 hourly dosing is likely to be
necessary
Dooley et al., J Acquir Immune Defic Syndr 2013;62:21–27
Integrase inhibitors- in adult HNVs
tenofovir alafenamide (TAF) - in adult HNVssubstrate of the drug transporters P-glycoprotein, OATP1B1, OATP1B3 and BCRP; and also (minimal) CYP3A4. Rifampicin induces CYP3A4, P-gp, and BRCP (and OATP).
TAF Twice Daily + RIF vs. TAF Once Daily
TAF Once DailyMean (%CV)
TAF Twice Daily + RIF, Mean (%CV)
GLSM Ratio (90% CI)
TAF - plasma AUC 0-24, ng*h/mL
345 (52) 290 (48) 85.8 (69.7 to 106)
TFV - plasma AUC 0-24, ng*h/mL
348 (20) 277 (19) 79.9 (73.1 to 87.3)
Intracellular TFV-DP AUC 0-24, fmol*h/106
cells 76.3 (58.7 to 99.2)
Custodio JM et al. 16th European AIDS Conference. October 25-27 2017, Milan
cobicistat – in vitroa relatively specific CYP3A4 inhibitor
no ARV activityno inducing effecteasier to co-formulate with PIsa substrate of CYP3A4, which rifampicin induces
O Roberts, et al., CROI 2016
darunavir + rifampicin - in silico
Siccardi et al., CROI 2015 PaediatricPOPULATION
PK model
PREDICTED DOSES
data pooling
ADULT DATA
PBPK
2nd-line TB drugs & ART
Effect of rifampicin and efavirenz on moxifloxacin concentrations when co-
administered in patients with drug-susceptible TB
EFV reduced MXF AUC by 30%
J Antimicrob Chemother. Published online February 08, 2017. doi:10.1093/jac/dkx004
Naidoo 2017
Conclusions
• ART with rifampicin-based TB treatment in children > 3 y: – 1st-line: use standard doses of EFV– second-line/need PI/r: LPV/r + extra ritonavir (1:1 ratio) – research gaps: double doses LPV/r tablet
(PK & safety) 12 hrly integrase inhibitor (doubled daily dose)12 hrly TAF (doubled daily dose)DRV/r doses with rifampicin
• ART for children < 3 y with TB:– LPV/r + extra ritonavir (1:1 ratio) – research gaps: 3 NRTIs (e.g. children virologically suppressed on 1st-
line regimen)12 hrly integrase inhibitor (doubled daily dose)12 hrly TAF (doubled daily dose)
• Research to support feasible co-treatment approaches in children is LAGGING increasingly far behind!