RITONAVIR INTERARITONAVIR INTERACTIONS AND SIDE ECTIONS AND SIDE E

FFECTSFFECTS

Present by Present by PEERAKARN BANJERDK PEERAKARN BANJERDK

IJIJ

OUTLINEOUTLINE• Introduction

• HIV Therapy

• Types of HIV-drugs

• Protease Inhibitors work

• Ritonavir• Pharmacology

• Drug Interactions

• Side effects

• Conclusion

INTRODUCTIONINTRODUCTION

Why is the “HIV Therapy” called “multiple therapies”?Ans. : Immune systemWhat is the “medical problem”?Ans. : Drug interactionsHow many types of HIV-drugs?Ans. : 3 Types

Types of HIV-drugs

2 main groups1. Reverse Transcriptase 1.1 Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

zidovudine (AZT)didanosine (ddI)

1.2 Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

nevirapine delaviridine

2. Protease Inhibitors (PIs)indinavirritonavir

What is HIV protease?What is HIV protease?

How do protease inhibitors work?

How do protease inhibitors differ from other available anti-HIV drugs?

OUTLINEOUTLINEIntroductionRitonavir

PharmacologyDrug InteractionsSide effects

Pharmacology

• Block maturation of virus • By interfering

• Act at the stage of HIV replication cycle

• Produce resistance• Bound plasma 98-99%• Cross resistance

• combine with NNRTIs or NRTIs

• combine with PIs Cross resistance

RITONAVIR

OUTLINEOUTLINEIntroductionRitonavir

PharmacologyDrug InteractionsSide effects

What types of other medications can interact with PIs?Ans.1 : HIV-HIV drugs

- Combination Therapy- Double-Drug ; PIs + PIs , PIs +

NRTIs- Triple-Drug ; PIs+PIs+NNRTIs

Ans.2 : HIV-Other drugs ; PIs+Antivirals

Combinations & Interactions

RITONAVIR

Drug Interactions

• Metabolized by P450 at the liver • Combine with competition drugs ; can occur

1. Metabolism of these drugs

2. Concentration of Ritonavir and these drugs

RITONAVIR

Between Other drugs and RitonavirInteracting Drugs Effect Mechanism

Group of drugs AmiodaroneAstemizoleBeperidilCisaprideClozapineErgotamineRifabutin etc.

Increase plasma con. ofantiretroviralPotential for serioustoxicitiesDo not coadminister

EtoposideLovastatinRifampinFentanyl etc.

> 3X increase AUC of drug CYP3A4 inhibitionby ritonavir

AmitriptylineFluoxetineHaloperiolPindodol

1.5-3X increase AUC ofdrug

CYP2D6 inhibitionby ritonavir

KetoconazolePhenobabitalDigoxin etc.

Possible increase AUC ofdrug

Unknown(1998)

DRUG INTERACTION

http://www.hivinsite.UCSF.edu/topics/research_advances/2098.339b.html

Between Other drugs and PIsDrugs

AffectedIndinavir

(IDV)Ritonavir

(RTV)Saquinavir

(SQV)*Nelfinavir

(NFV)Amprenavir

(APV)Antifugals:Ketoconazole

Levels :IDV 68%

Levels :Keto. 3X

Levels :SQV 3X

No doseadjustmentnecessary

Levels :APV 31%Keto. 44%

Antimyco-bacterials:Rifampin Levels :

IDV 89%Levels :RTV 35%

Levels :SQV 84%

Levels :NFV 82%

Levels :APV 82%No changerifampin

Rifabutin Levels :IDV 89%Rifabutin 2X

Levels :Rifabutin 4X

Levels :SQV 40%

Levels :NFV 32%Rifabu. 2X

Levels :NFV 82%Rifabutin 193%

http://www.thebody.com/hivatis/agents1/table14.html

DRUG INTERACTION

Between PIs and PIs

DrugAffected

Ritonavir(RTV)

Saquinavir(SQV)*

Nelfinavir(NFV)

Amprenavir(APV)

Indinavir(IDV)

Levels :IDV 2-5X

Levels :IDV no effectSQV 4-7X#

Levels :IDV 50%NFV 80%

Levels :APV 33%

Ritonavir(RTV)

- Levels :RTV no effectSQV 20X+#

Levels :RTV no effectNFV 1.5X

Levels :APV 2.5X

Saquinavir(SQV)

- - Levels :SQV 3-5XNFV 20%#

Levels :APV 32%

Nelfinavir(NFV)

- - - Levels :APV 1.5X

* Invirase or Fortovase , + Conducted with Invirase , # with Fortovase

http://www.thebody.com/hivatis/agents1/table15.html

DRUG COMBINATION

OUTLINEOUTLINEIntroductionRitonavir

PharmacologyDrug InteractionsSide effects

Adverse Drug ReactionSIDE EFFECTS

http://www.utoledo.edu/pharmacy/clinical/aids.html

Name(s) Ritonavir(RTV)

Indinavir(INV)

Saquinavir(SQV)

Nelfinavir(NFV)

Vomiting Nausea Diarrhea Numbness (mouth) Asthenia & Anorexia Fatigue /Tire Taste disturbance Increase liverTransminases

Rash GI problems Nephrolithiasis(Kidney stone)

http://www.iapac.org/clinmgt/avtherapies/patient/proinbk.html#top

HIV Drugs -ToxicitiesHIV Drugs -Toxicities

SIDE EFFECTS

HIVDrugs

Pancreatitis Nephrotoxicity Hepatotoxicity Rash Diarrhea

Ritonavir

Indinavir Nelfinavir AllProteaseInhibitors

http://www.thebody.com/hivatis/agents1/table16.html

OUTLINEOUTLINEIntroductionRitonavir

PharmacologyDrug InteractionsSide effects

Conclusion

CONCLUSIONSCONCLUSIONS

Protease Inhibitors can cure or not!Combination ; more efficiencySide effects ; different waysResistance ProblemsCross resistance problems

THE ENDTHE END THANK YOU THANK YOU

• Dr. SUVIT Dr. SUVIT• Dr. MARIA Dr. MARIA• Mr. SOMJERD Mr. SOMJERD

• CRI OFFIER & OUR CLASS CRI OFFIER & OUR CLASS…………......

Advantages & Disadvantages ofAdvantages & Disadvantages ofClass-Sparing RegimensClass-Sparing Regimens

SIDE EFFECTS

Regimen PossibleAdvantages

PossibleDisadvantages

Drug InteractionComplication

Impact on FutureOptions

PI-basedHAART

-Well document-Require multiplemutations-2 step inhibitors;RT & PI

-Lipodystrophy,hyperlipidemia andinsulin resistance-Difficult to use

-Inhibition ofP450 partway(not much)

-Save NNRTIs foruse in treatmentfailure-cross resistancewith other PIs

NNRTI-basedHAART(PI-sparing)

-PI relate sideeffects-Easier to use

-End pointunknown-Single Resistance

-Fewerinteractionproblems

-Save PIs for lateruse-cross resistance

Triple NRTIand PI-sparing

-Easier to use-Side effect (+PIand NNRTI)-Not confer crossresistance

-End pointunknown-High baselineviral load

-General druginteractionproblems

-Save both PI andNNRTI , later use-Limited crossresistance inNRTI

http://www.thebody.com/hivatis/agents1/table7.html