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!