1. Can Pharmacology Help? Peter L. Anderson, Pharm.D.
University of Colorado
Anschutz Medical Campus

2. Conflict of Interest
PLA receives research grants and contracts from Gilead Sciences, paid to his institution.

3. Future PrEP Pharmacology
Long Acting
CAB, VRC01 bNAbs, delivery systems (e.g implantable TAF)
New orals F-TAF
TDF-FTC in control arms
I will focus on long acting using CAB and VRC01 as examples. Same principles apply for implantables.

4. PrEP Pharmacology goal
Concentration-response & surrogate measures for effects
Dose-effect modelling
Starting and Stopping
Fill knowledge gaps

5. Conc-effect ingredients
Objectives
Conc-effect ingredients
iPrEx trial data
STRAND study data
LA, F/TAF
Long T-1/2 (hair/TFV-DP); gradients; proximity to HIV exposure
Phase I DOT to define conc/adherence/dosing (include tissue)
Phase III regression model for conc-effect √ √
Corneli. JAIDS Liu PLOS One Castillo-Mancilla ARHR Grant Lancet ID Landovitz. IAS Cottrell JAC 2017.

6. MSM Conc-effect 86% RR 100% RR (95%CI 86-100) (21%-99%)
IPERGAY; 86% (CI 40,98) efficacy,
average of 3.75 doses week

7. Preliminary Plasma Surrogates LA
CAB
VRC01
10mg/kg
q 8weeks
CAB (mcg/mL)
VRC01 (mcg/mL)
Long half life
Captures past dosing overlapping with HIV exposure.
The only way we are going to. get real surrogates is retrospectively
4 X PAIC90 (664ng/mL)
derived in HIV infected/pre-clinical
1 mcg/mL
derived in vitro/pre clinical
Also need concentration – resistance thresholds, which may be different…
Spreen, HIV Clin Trials. 2013; Landovitz. HPTN Andrews Science Markowitz. Lancet HIV 2017; Huang, MAbs. 2017

8. Genital & rectal distribution (gap)
TAF 2-10-fold lower vs TDF (as TFV-DP)
Cannot use TDF surrogates for TAF
CAB low 10-20%
Inform importance of systemic vs tissue conc
TAF – TFV is 2-10 fold lower in female genital and rectal vs TDF
Conc in blood for TAF or TDF in a pod may not work the same oral because oral will deliver some to the rectum
Hendrix Lancet HIV Cottrell JAC Spreen JAIDS Cottrell. Expert Opin Drug Metab Toxicol. 2015

9. How Pharmacology can help
Long t-1/2, Phase I PK, Phase III conc-effect
CAB – LA conc-effect & conc-resistance
Starting-stopping
How long to cover tail
Known surrogates for TDF-FTC control condition
Roadmap for F-TAF (but TDF surrogates do not extrapolate to F-TAF)
Rectal/genital drug distribution may help interpret outcomes
Long half life
Captures past dosing overlapping with HIV exposure.

10. Thank you… Colorado Antiviral pharmacology laboratory LR Bushman
J Castillo-Mancilla
DV Glidden
RM Grant
AY Liu
Susan Buchbinder
JJ Kiser
S MaWhinney
S Seifert

11. Residual ring vs HIV protection
Residual dapivirine & “dose-response” for HIV risk reduction.
MTN 025 monitoring residual ring.
Average drug release per day (mg/day)
E Brown, (IAS AIDS 2016). Abstract TUAC0105LB.

12. Surrogate for FTC-TDF in MSM
~2500 person years (37 cases): IPREX OLE (28 cases); ATN110/113 (7 cases); PrEP-DEMO (2 cases)
Infections (out of 37)
# of Breakthrough
IPERGAY; 86% (CI 40,98) efficacy,
average of 3.75 doses week
HIV risk reduction (OLE):
(95% CI)
44% (-31,77)
84% (21,99)
100% (86, 100)
Adherence interpretation:
No dosing
< 2 doses/wk
2-3 doses/wk
≥4 doses/wk
DBS (TFV-DP fmol/punch):
BLQ
BLQ - 349
≥700

13. Adherence Shows experimental conditions met
Correlates with trial efficacy
Brief snapshots in time
Relevance for LA?
Fonner AIDS 2016

14. Starting stopping (gap)
Half-life
Onset: ASAP
minutes
Duration: probably depends on if any replication occurred (so onset)…
Not clear if vaginal and rectal same…
1 day
6 days
15 days
15 days
5 half-lives
44 months
Silicano. ; Tsai J Virol 1998

15. MSM conc-effect > 95% RR for ≥ 4 doses/wk
STRAND DOT PK
> 95% RR for ≥ 4 doses/wk
Dose-effect modeling consistent with IPERGAY results….
Need three things.
Long half life moiety
Phase I to inform dose-adherence relationship
Concentration-effect data from trials. Need a fair number of infections with drug concentrations.
Captures past dosing overlapping with HIV exposure.
4-day half life…
Liu. PLOS One Glidden Lancet HIV Anderson STM Seifert CID Grant Lancet ID 2014.

16. PrEP Pharmacology Human conc-response retrospectively.
Use HIV-infection dose-response.
No surrogate of efficacy similar to HIV-RNA for treatment.
Dose finding not practical.
Drug concentration surrogates identified retrospectively from clinical studies.
Rowland and Tozer. LLW 2011
Hendrix. Lancet HIV. 2016