Chemsex Drug-Drug Interactions

ChemSex Drug-Drug Interactions

José Moltó, MD, PhD Fundació Lluita contra la Sida, Badalona. Servei Malalties Infeccioses, Hospital Universitari Germans Trias i Pujol, Badalona.

4th European Workshop on Healthy Living with HIV

Barcelona, 13th September 2019 Disclosures

Within the last 12 months, I have received research funding, consultancy fees, and lecture sponsorships from and have served on advisory boards for various laboratories: - Gilead Sciences - Janssen-Cilag - MSD - Viiv Healthcare 1980 2020 Chemsex, ‘Party 'n Play" culture (PnP) or H&H culture ("High & Horny").

Use of any combination of drugs that includes methamphetamine, mephedrone (and other cathinone) and/or GHB/GBL used specifically for sex, by gay and other men who have sex with men.

(Sept) It is NOT only recreational drug use. It is a specific form of recreational drug use.

McCall H et al. BMJ 2015 McCall H, et l. BMJ 2015;351:5790. Drugs commonly used in chemsex

Alcohol Cocaine

GHB Crystal

Poppers

Ecstasy Mephedrone Sildenafil

Ketamine Apps Epidemiology. MSM; HIV+

Daskaopaoulou M, et al. Lancet 2014 Daskaopaoulou M, et al. Lancet 2014 Pufall EL, et al. HIV Med. 2018 Pufall EL, et al. CROI 2016 Gonzalez-Baeza A, et al. AIDS Patient Care STDS. 2018 Ryan P, et al. GESIDA 2016 Chemsex Potential negative consequences

STDs Psychiatric cART adherence transmission disorders DDIs & Overdose An observed rise in g-hydroxybutyrate- Substance misuse-related poisoning associated deaths in London:Evidence to suggest deaths, England and Wales, 1993–2016 a posible link with concomitant rise in chemsex

Hockenhull J, et al. Forensic Sci Int. 2017. Handley SA, et al. Drug Science, Policy and Law 2018 Chemsex & cART DDIs & Overdose risk

DDIs between recreational drugs and ARVs. Rationale

• Some ARV drugs may inhibit drug transporters and metabolizing enzymes – Boosters (RTV or COBI)

• PK of recreational drugs may be affected by ARV drugs – Special risk for relevant DDIs DDIs between ART and recreational drugs Sources of information

Desirable • Clinical trials – Lacking – Ethical issues

• Clinical reports – Under-reported

• Theoretical rationale Quality of Evidence: Very Low – In vitro data Coadministration has not been Available studied but is expected to……. Theoretical rationale for potential for DDIs

Erectile Methamphe- Drug Mephedrone GHB Ecstasy Cocaine dysfunction Ketamine tamine agents

Metabolic Esterases CYP2D6 CYP2D6 CYP2D6 CYP2D6 CYP3A4 CYP3A4 pathway 10% CYP3A4

High risk for DDIs!!

≈155 ng/mL ≈144 ng/mL

Cmax (ng/mL) Ctau (ng/mL) AUC (ng.h/mL) COBI 1700 35 12300

RTV 840 80 6600 German et al. 12th IWCPHT 2011 • Ritonavir and Erectile Dysfunction Agents

Co-med dose RTV dose Effect on co- Effect on med AUC co-med Cmax Sildenafil 100 mg (sd) 500 mg bid x11 x4 Tadalafil 20 mg (sd) 200 mg bid x1.24 <-> Vardenafil 5 mg (sd) 600 mg bid x49 x13

• Ketamine

Norvir. Prescr info. Zhou J, et al. Int J STD AIDS 2013 Theoretical rationale for potential for DDIs

Erectile Methamphe- Drug Mephedrone GHB Ecstasy Cocaine dysfunction Ketamine tamine agents

Metabolic Esterases CYP2D6 CYP2D6 CYP2D6 CYP2D6 CYP3A4 CYP3A4 pathway 10% CYP3A4

≈7139 ng/mL ≈2016 ng/mL

German et al. 12th IWCPHT 2011 Case reports on DDI between high-dose RTV and GHB/MDMA

• Fatal interaction between ritonavir and MDMA. Henry, JA, Hill IR. Lancet, 1998, 352:1751–2. – Case report of fatal interaction of ecstasy and ritonavir. Blood concentration of MDMA post mortem was 4.56 mg/L (~10x higher than anticipated).

• Life-threatening interactions between HIV-1 protease inhibitors and the illicit drugs MDMA and gamma-hydroxybutyrate. Harrington RD, Woodward JA, Hooton TM, et al. Arch Intern Med, 1999, 159:2221–4. – Case report of a patient who reported prolongation of the agitation effects of MDMA (29 h). The effect of MDMA was much longer than when similar doses had been taken prior to the use of ritonavir and saquinavir. – Patient took GHB to counteract effects of MDMA and experienced a life-threatening reaction. – Changes in the magnitude of effect attributed to protease inhibitors. Risk for DDIs at boosting doses??

Erectile Methamphe- Drug Mephedrone GHB Ecstasy Cocaine dysfunction Ketamine tamine agents

Metabolic Esterases CYP2D6 CYP2D6 CYP2D6 CYP2D6 CYP3A4 CYP3A4 pathway 10% CYP3A4

≈7139 ng/mL ≈2016 ng/mL

Cmax (ng/mL) Ctau (ng/mL) AUC (ng.h/mL) COBI 1700 35 12300

RTV 840 80 6600 German et al. 12th IWCPHT 2011 Effect of low-doce ritonavir (100 mg bid) on The effect of cobicistat on cytochrome P450 2D6, the activity of cytochrome P450 2D6 in 2B6, and P-glycoprotein using phenotipic probes healthy volunteers

AUC x1.26 (1.13-1.40)

⚫ Desipramine alone

 Desipramine + ritonavir

AUC x1.58 (1.35-1.84)

Aarnoutse et al. CPT 2005 German et al. 12th IWCPHT 2011 Pharmacodymamic interactions

→Cocaine + RPV… QT prolongation

→ Combinations of ≥2 stimulants Hypertermia, dehydratation, agitation, tachycardia…

→ Combinations of ≥2 depressants Respiratory depression/coma GHB/GBL + alcohol Ethanol is present in most GHB intoxications

Ethanol Amphetamine Cocaine Opiates Marijuana

Cin et al. 39% 17% 5% 3% 3% (n=88) Li e al. 86% 0% 71% 0% 14% (n=7) Garrison et al. (n=57) 63% 50% 40% 10% 60%

Elsohly et al (n=48) 33% 13% 8% 4% 21%

Mason et al. Academic Emergency Medicine 2002 GHB and Ethanol Effects and Interactions in Humans

Placebo

Ethanol (0.6 g/kg)

GHB (50 mg/kg)

Ethanol + GHB

Thai et al. J Clin Psycopharmacol 2006 Conclusions • ChemSex is common among MSM (especially among HIV+) • Potential negative consequences STDs; Psychiatric disorders; Overdose • Chemsexers on cART may be exposed to higher risk of DDIs Boosted ARTs CYP3A4 vs. CYP2D6 substrates • Quality of evidence is still very low Clinical trials lacking Simulations based on PBPK modelling Case reports www.clinicalcasesDDIs.com

Technical Secretariat:

Sponsored by: [email protected] OBJECTIVES www.clinicalcasesDDIs.com

Open-access web page on clinical cases on drug interactions between drugs used by PLWH (including OTC, recreational drugs or complementary treatments). The page can be used for:

- Reporting new clinical cases on drug combinations

- Searching for clinical cases on specific combinations.

- Share information on real-life experience about drug combinations that may be used by PLWH in the clinic.

Developed by: Sponsored by: 2015-2018 Thank you!