9. PKPD of ARVs

Does PK or PD describe ADME?

PK: The study of how the body affects the drug

What is PD?

How the drug affects the body. e.g. drug concentration —> response?

What is PG (pharmacogenomics?)

Polymorphisms in UGT1A1 gene appear to influence plasma levels of what ARV drug?

Atazanavir

What ARVs are the only IVs?

Zidovudine (AZT/ZDV) and Ibalizumab (IBA)

What are the only ARV available as SQ?

Enfurvitide (ENF/T-20), Lenacapavir (LEN)

What ARVs are available as IM?

LA RPV/CAB gluteal Q1-2M

What factors affect drug absorption?

What is the effect of food on gastric pH?

Increases pH in stomach (lowers acid) immediately upon ingestion, acting as a buffer that makes the stomach contents less acidic (e.g., rising from pH 1 to over 4.5). This effect is temporary, as the meal subsequently stimulates gastric acid secretion, which eventually lowers the pH back to highly acidic levels over the next 3-4 hours

It also delays gastric emptying

What ARV(s) must be taken on an EMPTY stomach? and why?

Efavirenz (EFV) (high fat increases absorption —> toxicities)

What ARV(s) must be taken WITH FOOD?

NNRTI: RPV Rilpivirine (H2RAs 12 hours before or 4 hours after / Antacids 4 hours before or 2 hours after RPV. PPIs CId) (500+ calories, fat)

PI: ATV/b, DRV/b

INSTI: EVG/b

If RPV absorption is reduced by antacids (i.e. it needs acidic environment), then why does taking it with a meal help absorption? I thought meals initially alkalinize gastric pH?

Rilpivirine (RPV) absorption is indeed highly dependent on an acidic environment (low pH) to dissolve properly, and taking it with a meal helps because it relies on the secondary drop in gastric pH after the initial rise from eating a meal. That significant drop in pH later on, is what facilitates RPV absorption and dissolution.

What ARVs are either CId or must be separated from antacids?

Rilpivirine (RPV) - Separate from H2RAs/antacids. NO PPIS AT ALL. (TAKE WITH FOOD)

ATV - Separate from H2RAs/antacids/PPIs. Needs highly acidic environment

What ARVs must be separated from Cations?

[Mg+/Al+/Ca+/Fe+]

• Oral INSTIs (they chelate to these)

• RAL completely CId with any Al+/Mg + products (Calcium ok with caveats)

Per DHHS, Cation supplements/laxatives must be taken 2 hours after INSTIs or 6 hours before INSTIs

OR alternatively, INSTIs and cation supplements can be taken simultaneously with food.

This is because food inhibits the chelation process in the stomach

RAL completely CId with any Al/Mg products/supplements. Calcium carbonate antacids (tums) MAY be taken with RAL under what circumstances?

BID RAL is okay with calcium carbonate antacids

RAL 400mg BID (yes)

RAL 1200mg QD (no)

Which ARVs must be taken with regards to food and/or PPIs?

Efavirenz EFV - EMPTY stomach

Rilpivirine (RPV) - WITH FOOD (500cal or more) Separate from H2RAs/antacids. NO PPIS AT ALL.

ATV - SEPARATE from acid-reducing agents

ORAL INSTIs: Separate from cations (Al/Ca/Mg) products, RAL CId with Al/Mg products

Which one: Kaletra tablets or solution needs to be taken with food?

Oral solution requires food for proper absorption. Tablets can be taken with/without food.

ARV tablets/capsules you cannot crush or open?

Kaletra tablets: Crushing tablets significantly reduces exposure to both components by around 50% vs. swallowing whole. Should be given in solutions.

Proteins in the blood: Albumin binds ____ drugs. Alpha 1 Glycoprotein binds _____ drugs.

Albumin binds ACIDIC drugs

A1GP binds BASIC drugs

ARV Drugs that have this property may improve neurocognitive HIV deficits?

Drugs with better CNS penetration

What is an HIV “sanctuary site”?

A compartmentalized area where HIV can undergo viral replication with higher potential to select for RAMs due to suboptimal drug penetration into that specific site. Such as male/female genital track and CNS.

What score categorizes ARVs by CNS penetration?

“CPE” scores

CNS Penetration-Effectiveness Score

Rates ARVs 1(low CNS) to 4 (high CNS)

What ARVs have high CPE score of 4?

AZT, NVP, IND/r, DTG

Other than Liver, where else are CYP enzymes found?

INSTESTINES

also, to lesser extent, in smooth endoplasmic reticulum of cells throughout the body

Ritonovir and Cobi inhibit which CYP?

CYP3A4

Which ARVs is COBI FDA approved to boost?

EVG/ATV/DRV

Which is more selective to CYP3A4 and thus has less potential for off-target DDIs? Cobi vs. RTV?

COBI

Do both COBI and RTV have anti-HIV activity?

NO. only RTV. and 100mg booster dose is considered subtherapeutic.

What PK parameter do RTV/Cobi primarily enhance, and how is this beneficial?

Primarily enhance TROUGH levels of ARVs which reduces the risk of selection of RAMs

Also:

Minimizes need for food requirements and

reduces DDIs with inducers of CYP3A4.

reduced dosing frequency

increased forgiveness with missing doses (increased barrier to resistance)

How are INSTIs metabolized?

What is P-gp?

a cellular protein pump involved in transporting molecules in/out of the cell. found extensively in the intestine. PIs are major P-gp substates.

overexpression of Pgp may result in lower ARV concentration.

Ritonovir is a potent P-gp inhibitor

Substrates for P-gp

All PWH should have SCr monitored AT LEAST _____

every 6 months.

Some experts advocate the use of TDM to monitor ART. What are the limitations of routinely using TDM for ART?

Therapeutic Drug Monitoring

Does TAF or TDF have longer half life?

In plasma, TDF is much LONGER, 12 hrs vs. 30 minutes

TAF has a SHORT plasma half life of 30 minutes, because it all goes into the cell. It has an intracellular half life of active metabolite TFV-DP is 150-180 hours.

PK Table of NRTIs

PK properties of NNRTIs

Which ARVs are inducers of CYP3A4?

Efavirenz, Etravirine, Nevirapine

PK table PIs

Numerous drug interactions occur with which class of ART? and why?

PIs because they are CYP3A4 substrates.

INSTI PK Table

How is RAL dosed?

When RAL given with rifampin, what does must you use?

RAL 800mg BID

IBA PK TABLE

LA CAB/RPV PK TABLE

PK FOSTEMSAVIR TABLE

Temsavir primarily metabolized by esterases

CId with rifampin

PK TABLE LENACAPAVIR

Q6M SQ