Clinical Pharmacology of Integrase...
Transcript of Clinical Pharmacology of Integrase...
Saye Khoo
University of Liverpool, UK
Clinical Pharmacology of Integrase Inhibitors
Declaration of Interestswww.hiv-druginteractions.org & www.hep-druginteractions.org
Receives sponsorship from AbbVie, Merck, BMS, Janssen, Gilead, ViiV.Editorial content remains independent.
Research funding, travel grants, speakers bureau from Gilead, AbbVie, ViiV, Merck, Janssen
See https://www.liverpool.ac.uk/translational-medicine/staff/saye-khoo/external-engagement/
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▪ Pharmacology of InSTIs (RAL, EVGc, DTG, BIC)
▪ Special Populations, with focus on pregnancy
▪ Drug Interactions
▪ RAL od versus bd
Integrases - Pharmacology
RAL EVGc DTG BIC
Dose 400mg bd or
1200mg od
150mg qd with
booster
50mg qd or bd
(experienced)
50mg od
Food Effect Significant
C12 66-100%) with
mod-high fat
food variability
No restrictions
Significant
AUC 36-91% with
mod-high fat
Take with food
Moderate
AUC 33-41% with
mod-high fat
Take with food if
TE, or DDI
Mild-Moderate
AUC 24% with mod/high
fat
No restrictions
Metabolism UGT1A1 CYP3A
UGT1A1/3
UGT1A1
(CYP3A 10-15%)
>90% metabolised
Substrate of CYP3A,
UGT1A1
Protein binding 83% 99% 99% 99%
Half life 9h 12.9h 14h 17.3h
Pharmacogenetics UGT1A1 *28/*28
AUC 41% C12 91%
Effect unlikely UGT1A1 PM
AUC 41%
Significant effect
unlikely
Integrases – Special Populations
RAL EVGc DTG BIC
Effect on eGFR V small (5mL/min)
reduction in eGFR
(cobi effect) Modest (13-15mL/min)
reduction in eGFR
(OCT-2 inhibition)
Modest reduction in
eGFR
(OCT2 / MATE1
inhibition)
Renal Impairment No adjustment FDC - eGFR
Genvoya >30
Stribild >70
No adjustment FDC eGFR >30
No data <15ml/min
(<1% renal excretion)
Hemodialysis No data; avoid
dosing before
dialysis
FDC – avoid No data, no difference
expected
No data
Cirrhosis (CPT A/B) No adjustment No adjustment No adjustment No adjustment
Severe (CPT C) Caution Not recommended Caution Not studied
Integrases – Special Populations
RAL EVGc DTG BIC
Swallowing Chewable tablets,
granules
(bioavailability)
Cannot be
chewed or
crushed
Crushable, can be
given with NG feeds
Granule being
developed
( bioavailability)
Not recommended
Children Licensed from 4
weeks
Not licensed <18,
avoid <6
Not licensed <12 Insufficient data
<18y
Pregnancy Reasonable data;
Preferred
(DHHS 2017)
Limited data;
Not recommended
(DHHS 2017)
Preliminary Data;
WOCBP – use
contraception
(FDA/EMEA 2018)
No data
www.hiv-druginteractions.org
Integrases – Special Populations
RAL EVGc DTG BIC
Swallowing Chewable tablets,
granules
(bioavailability)
Cannot be
chewed or
crushed
Crushable, can be
given with NG feeds
Granule being
developed
( bioavailability)
Not recommended
Children ≥ 4 weeks ≥ 6y of age
(≥ 25kg)
≥ 6y of age ≥ 18 years
Pregnancy Reasonable data;
Preferred
(DHHS 2017)
Limited data;
Not recommended
(DHHS 2017)
Preliminary Data;
WOCBP – use
contraception
(FDA/EMEA 2018)
No data
ARV exposure in Pregnant Mothers and their Infants
MOTHERchanges in drug
exposure (T3)
MOTHERBM penetration
of ARVs
BABYAntepartum & peripartum
exposure of ARV
BABYARV exposure through
breastfeeding
Third Trimester Exposures (vs PP) of HIV Drugs
Stek et al . JIADS 2015;70:33
Colbers et al AIDS 2013,27:739
Moodley et al JID 1998; 178: 1327
Le et al. AVT 2015;20:507
Mirochnick et al CPK 2004;43:1071
Blonk et al. Clin Infect Dis. 2015;61:809
Colbers et al CID 2015:61:1582
Else et al. AAC 2012:56(2):816
Best et al. HIV Med 2015;16:502
Mulligan et al. CROI 2016
Best CROI 2017
Rimawi et al. AC 2017
ABC
FTC
TDF
ETR
EFV
NVP
ATV
DRV (od)
DRV (bd)
FPVr
LPVr (sgc)
LPVr (tab)
RTV (LPV)
MVC
RAL
EVG
Cobi
DTG
REDUCED in T3 INCREASED in T3
0.5 0.75 1.51.0
0.43
0.58
Elvitegravir and Cobicistat in Pregnancy
Cord blood: maternal plasma concentrations
0% 50% 100%
* unbound
Schalwijk et al. AIDS 2015;30:1239
Fayet-Mello Antivir Ther. 2013;18(2):171
Yeh et al AAC 2009 Jun;53(6):2367
Cressey et al . JAIDS 2012 Mar 1;59(3):245
Mulligan et al. Front Pharmacol 2016 Aug 4;7:239
Watts et al. JAIDS 2014 Dec 1;67(4):375
Blonk et al. Clin Infect Dis. 2015;61:809
NVP 50-80%
RPV 55%EFV
49%
ETR52%
3TC100%
TFV~100%
ZDV86%
ABC100%
FTC~100%
ATV 15%
DRV18%
FPV27%
LPV*41-57%
RTV15-55%
SQV 3%
IDV65%
RAL / DTG>=100%
MVC30%
T202%
UGT1A1 activity in neonates –Delayed Washout of RAL & DTG, but not EVG
▪ N = 19
▪ Cord: maternal ratio 1.48
▪ Highly variable elimination
▪ Median T½ 26.6h (9.3 – 184)
▪ (adult T½ typically 9h)
▪ N = 10
▪ Median T½ 34.5h (IQR 28.6-39.9)
▪ (adult T½ typically 14h)
RALP1097
DTGP1026s
Clarke et al, JAIDS 2014 Nov 1;67(3):310
Mulligan et al CROI 2016
Best CROI 2017
EVGcP1026s
▪ N = 16
▪ Median T½ 7.4h (IQR 3.1-7.5)
▪ Similar to typical adult T½
Delayed initiation of ART in Pregnancy
• PMTCT programmes report significant
rates of delayed ART initiation (3rd
trimester or labour)
• Most often relates to delayed diagnosis
• Study from Yunnan Province
• N = 1548 HIV+ pregnanciesARV in T1 or T2 63%
ARV in T3 17%
L&D or no ARV 20%
• Adverse impact on infant mortality
• Strong case for use of INSTI
0
1
2
3
4
5
0,1 1 10Adjusted RR of transmission
T1 or T2
T3
L&D or
no ART
7.01
7.55
Meyers et al. . PLoS ONE 2015;10(9): e0138104
RAL EVGc DTG BIC
Metabolism UGT1A1 CYP3A
UGT1A1/3
UGT1A1
(CYP3A 10-15%)
CYP3A & UGT1A1
Perpetrator of
DDIs
No effect on CYPs,
UGT or PgP
Cobi – inhibits
CYP3A +++,
(CYP2D6 & MATE1)
EVG –induces
CYP2C9
No effect on CYPs,
UGT or PgP
OCT2 - metformin
No effect on CYPs, or
UGT1A1
OCT2 - metformin
Divalent cations Al/ Mg contraindicated
Ca- not clinically
meaningful
Al/Mg antacids- ±2h
Multivits ±4h
Al/Mg/Ca/Fe/Multivits
take -6h or +2h
Fe – take with food
Al/Mg antacids-
take +2h. (EMEA – 2h
before BIC (with food)
Fe and Ca++ take with
food
Gastric pH pH dependent solubility
absorption with OMP
(+39%) / FAM (+45%);
no dose adjustment
No DDI expected No DDI expected No DDI expected
Integrases – Drug Interactions
** BIC unlicensed, data from published abstracts etc
Differences between RAL twice and once-daily
Rizk et al. CROI 2014
RAL 600mg reformulation (vs 400mg)
• Higher relative bioavailability
• Similar systemic PK thereafter
• Less variability
• Food effects similar/smaller
• Any potential impact on DDIs or special
groups ?
Differences between RAL twice and once-daily
RAL 400bd RAL 1200od Notes
Rifabutin ◆* ◆ * RBT (300od): RAL Cmin 20%
Rifapentine ◼* ◼* RPT weekly: RAL AUC 71%,
* RPT daily: RAL Cmin 41%
Rifampicin ◼ Not recommended
Carbamazepine ◼ Not recommended
Phenytoin ◼ Not recommended
Phenobarbitone ◼ Not recommended
Pregnancy ◆
BD dosing required
(DHHS Nov 2017)
T3: AUC 29%,
Cmin probably
Metformin, OCT2 and Dolutegravir / Bictegravir
• Both DTG and BIC are inhibitors of OCT2• Metformin is excreted unchanged in urine, mainly through OCT2
0,1
1,0
10,0
0 4 8 12
Co
nce
ntr
atio
n,
µg/
mL
Nominal Time, h
Metformin Alone, Period 1
Metformin + DTG 50 mg q24h
Metformin Alone, Period 3
0,1
1,0
10,0
0 4 8 12
Co
nce
ntr
atio
n,
µg/
mL
Nominal Time, h
Metformin Alone, Period 1
Metformin + DTG 50 mg q12h
Metformin Alone, Period 3
MET AUC +79%
DTG qd DTG bd
MET AUC +145%
M e t f o r m i n i n P l a s m a
T i m e , h
Me
tf
or
min
C
on
ce
nt
ra
tio
n, n
g/m
L
0 4 8 1 2 1 6 2 0 2 4
1 0
1 0 0
1 0 0 0
1 0 0 0 0
P l a c e b o
B / F / T A F
B/F/Taf od
MET AUC +39%
• Metformin-induced lactic acidosis rare
• Many cases (particularly fatalities) related to underlying conditions rather than metformin risk of LA with impaired GFR (<60ml/min; HR 6.37) particularly with high doses (>2g/d; HR 13.0) are also used
• Close monitoring when starting/stopping DTG
• Avoid high Metformin doses (eg 2g/day), especially in patients with eGFR<60COSMIC Study; Cryer Diabetes 2003
Stades J Int Med 255:179–187, 2004
Eppenga. Diabetes Care 2014
DDIs between HIV drugs and Hormonal Contraception
www.hiv-druginteractions.org/printable_charts
ATV/r DRV/r LPV/r EFV ETV NVP RPV RAL EVGc DTG BIC ABC XTC TDF
Estrogen Ethinylestradiol ↓19% ↓44% ↓42% ↔ ↓20% ↓25%
Progestins (COC)
Desogestrel ↑ ↑ ↑ ↓ ↓ ↓ ↑
Drospirenone ↑ ↑ ↑ ↓ ↓ ↓ ↑
Gestodene ↑ ↑ ↑ ↓ ↓ ↓ ↑
Levonorgestrel ↑ ↑ ↑ ↓ ↓ ↑ ↑
Norethisterone/-thindrone ↑ ↓14% ↓17% ↓ ↓19% ↑
Norgestimate ↑85% ↑ ↑ ↓64% ↓ ↓ ↑126%
Norgestrel ↑ ↑ ↑ ↓ ↓ ↑29% ↑
Progestins (POP)
Desogestrel ↑ ↑ ↑ ↓ ↓ ↓ ↑
Levonorgestrel ↑ ↑ ↑ ↓ ↓ ↑ ↑
Norethisterone (Norethindrone) ↑50% ↑50% ↑50% ↓ ↓ ↓ ↑
Progestins (Non-oral)
Etonogestrel (implant) ↑ ↑ ↑52% ↓63% ↓ ↓ ↑
Etonogestrel (CVR) ↑ ↑ ↑ ↓ ↓ ↓ ↑j
Levonorgestrel (IUD)
Levonorgestrel (implant) ↑ ↑ ↑ ↓57% ↓ ↑14% ↑
Medroxyprogesterone (depot)
Norelgestromin (patch) ↑ ↑ ↑83% ↓ ↓ ↓ ↑
Norethisterone/ -thindrone (depot)
Emergency
Levonorgestrel (emergency) ↑ ↑ ↑ ↓58% ↑
Mifepristone ↑ ↑ ↑ ↓ ↓ ↓ ↑
Ulipristal ↑ ↑ ↑ ↓ ↓ ↓ ↑
Interactions with Rifampicin
Time after dose (hours)
7
6
5
4
3
2
1
0
DT
G c
on
cen
trat
ion
(µ
g/m
L)
0 4 8 12 16 20 24
DTG 50 mg QD1,2
DTG 50 mg BID1,2
DTG 50 mg BID
+ RIF 600 mg QD1,2
REFLATE: HIV/TB coinfected
• RIF + RAL 400bd – slightly lower exposures(C0 0.46)
• RIF + RAL 800bd - overcompensated
RIFRAL (HIV-) RIF 3x/w + RAL
• HIV+ Rif (3x/w) Cmin 60%, restored by 800mg RAL
bd
RAL + RIF
• HIV- AUC 54% Cmin 72%
• DTG 50 bd + rif comparable Cmin
INSPIRING (CROI 2018) – 24w outcomes with
coinfection
DTG + RIF
Taburet et al. Clin Infect Dis. 2015 Oct 15;61(8):1328
Dooley et al. J Acquir Immune Defic Syndr 2013; 62:21–7
Reynolds et al. JAC 2015 Feb;70(2):550-4
Dooley et al. CROI 2018
DOSE at 50mg bd
DOSE at 400 or 800mg bd
Interactions with Rifampicin
BIC + Rif in healthy volunteers
• Even with bid dosing, BIC AUC 60%, Ctrough
~80%,
• A proportion of patients may fall below the paEC95
(target)
• Well-tolerated (FTC exposure approx doubled)
• BFTaf bid with RIF not recommended
BIC + RIF
BIC + Rifampicin not recommendedCustodio et al. CROI 2018 34
Interactions with TB medications
DTG EVGc RAL BIC EFV RPV DRVr ATVr TDF ABC (X)TC
Rifabutin ◆ ◼ ◆ ⚫ ◼ ⚫ ◼ ◼ ◆ ◆ ◆
Rifampicin ◼ ⚫ ◼ ⚫ ◼ ⚫ ⚫ ⚫ ◆ ◼ ◆
Rifapentine ◼ ⚫ ◼ ⚫ ◼ ⚫ ◼ ◼ ◆ ◆ ◆
Streptomycin ◆ ◼ ◆ ◆ ◆ ◆ ◆ ◆ ◼ ◆ ◆
Isoniazid ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆
Pyrazinamide ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆
Ethambutol ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆
Capreomycin ◼ ◼ ◼ ◼ ◆ ◆ ◆ ◆ ◼ ◆ ◼
Amikacin ◆ ◼ ◆ ◆ ◆ ◆ ◆ ◆ ◼ ◆ ◼
Kanamycin ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◼ ◆ ◼
Moxifloxacin ◆ ◆ ◆ ◆ ◼ ◼ ◆ ◼ ◆ ◆ ◆
Levofloxacin ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◼
Ethionamide ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆
Cycloserine ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆
PAS ◆ ◼ ◆ ◼ ◆ ◼ ◆ ◆ ◼ ◆ ◼
Bedaquiline ◆ ◼ ◆ ◆ ◼ ◼ ◼ ◼ ◆ ◆ ◆
Clofazimine ◆ ◆ ◆ ◆ ◆ ◼ ◼ ◆ ◆ ◆ ◆
Integrases and DDIs
▪ InSTI as PERPETRATORS: EVGc > DTG/BIC > RAL
▪ InSTI as VICTIMS:
Inducers eg Rifampicin, antiepilepticsDTG – consider 50bdEVG – avoidBIC – likely to be significantly affected (note Taf + Rif data from EACS)
InhibitorsATV or ATVr – will increase DTG, BIC, RAL exposures
▪ Managing DDIs
FDC (eg E/C/F/Taf, or B/F/Taf) ?DTG dosing with inducer AND InSTI-experienced ?
** BIC unlicensed, data from published abstracts etc
Summary
InSTIs likely to replace EFV in preferred regimens
• Efficacy & tolerability
• DDIs
• (cost)
Important needs to be addressed
• Pediatric use
• Pregnancy
• TB
• 2DR
• IRIS and CNS toxicity
Optimal deployment to maximise the useful therapeutic lifespan
• Prevention of resistance
• Transition from EFV-based regimens in LMIC