Question

Explain the following in relation to antiretroviral therapy: i. Pharmacodynamics ii. Pharmacokinetics iii. Pharmacogenomics iv. Drug availability during contraception use and pregnancy v. Drug-drug interactions during treatment

Answer 1

1. PHARMACODYNAMICS OF ANTIRETROVIRAL DRUGS:

Since antiretrovirals[ARV] are employed in the treatment of chronic infections like HIV/AIDS, they are intended for long term use, probably life long. Pharmacodynamics of those drugs are so studied with emphasis on the effects which is evident in the decline of viral load and improvement in the restoration of the deteriorating immunity. Combination therapies are always better than monotherapy. E.g. : a combination of ritonavir and Saquinavir has proven to possess strong antiretroviral activity.

2.PHARMACOKINETICS OF ANTIRETROVIRAL DRUGS:

• The pharmacokinetics of a drug deals with what body does to the drug which is very essential to study so as to avoid toxicity, prevent drug drug interactions and improve efficacy and bioavailability.
• Administration of combination of drugs showed improvements like: ritonavir was found to increase the bioavailability and prolong the elimination half-life of saquinavir.
• Indinavir as 66% plasma protein binding which is an advantage whereas the half life is short and systemic clearance is too high, so has to be taken in empty stomach.
• when given together, ritonavir improves the bioavailability and prolongs the elimination half-life of indinavir, similar to saquinavir.
• Trough concentrations of indinavir seems to be 4 folds higher when given with ritonavir, twice daily.
• The combination of protease inhibitors and NNRTIs is very attractive since both groups of drugs posses potent antiretroviral efficacy and they are not antagonistic in mechanism.
• Nelfinavir decreases AUC of dilavirdine.

3.PHARMACOGENOMICS OF ARVs:

• Pharmacogenomics of a drug reveals the genomic profile and that does the stratification of the patient population as likely responders, non responders, likely to have experience of ADRs, hyper sensitivity etc.
• The variation in the drug response is explained by the genetic variations in the genes associated with metabolism and transport of the drugs.
• HLA haplotype B and hypersensitivity to Abacavir is anexample for this.

4. ARVs with contraceptives:

ARV administration changes systemic levels of Hormonal Contraceptives, and vice versa, but the relevance of these changes in clinical aspect have not played out in large evidence based studies. It is a fact that proper birth control should be done in an HIV positive lady of reproductive age, but should be of proper clinical guidance and examination to avoid unwanted effects.

5. DRUG DRUG INTERACTIONS:

Expected drug interactions should be taken into consideration on selection of an ARV regimen. A wide and vast review of concurrant drugs can help in designing a regimen that minimizes unwanted interactions. The potential for those drug interactions should be checked on addition of any new drug (including OTCs) to the existing regimen. Mostly, drug interactions with ARVs are explainable via inhibition or induction of hepatic metabolism of the drug.

Drug absorption of ARV is affected by:

• Antacids

• polyvalent cations containing drugs

• inducers and inhibitors of CYP3A4 or efflux transporter P-glycoprotein

Drug metabolism is affected by:

• cytochrome P450 enzyme system (major fraction of drugs)

• UGT1A1 enzyme mechanism in phase 2 metabolism

Pharmacokinetic enhancers are employed to enhance exposure of ARV by concurrently administering a medication that inhibits enzymes which metabolize ARV.