Pharmacological determinants of long-term treatment success

Transcription

1 Professor David Back Liverpool, UK Pharmacological determinants of long-term treatment success

2 Pharmacological Issues with Antiretroviral Therapy Intrinsic potency Bioavailability Effect of food and other drugs on absorption Protein binding Plasma half-life Intracellular half-life Sanctuary sites Drug interactions unfavourable pharmacoenhancement Tolerability and toxicity Dosage regimens in special patient groups Intracellular activation

3 Three Key Parameters Potency of drug against the virus Protein binding must have adequate concentration in vivo of free drug In vivo pharmacokinetics (C max, C min, AUC, half-life)

4 Activation of Nucleoside Analogues Adenosine ZDV Thymidine ABC Adenosine Phosphotransferase ZDV-MP 3TC-MP Cytosolic Enzyme ZDV-DP 3TC-DP Kinase ZDV-TP ddc-tp 3TC-TP Kinase dda-tp CBV-TP

5 Metabolic Pathways of Cellular Nucleosides DPD 3 AMP IMP MA 1 GMP RBV Cytidine dcmp Salvage Pathway (<20%) dump Thymidine dtmp ADP dadp HU GDP dgdp De Novo Pathway 2 2 CDP dcdp dtdp datp dgtp HU dctp dttp 1. IMP dehydrogenase 2. Ribonucleotide reductase 3. Carrier-mediated transport

6 MRP4: A previously unidentified factor in resistance to nucleoside-based antiviral drugs Because MRP is expressed in normal tissues and because HIV can infect a variety of cell types, high levels of MRP4 expression at some anatomical sites may allow growth and evolution of drug-resistant HIV by decreasing the amount of intracellular drug to levels below that necessary to inhibit HIV replication. Schuetz et al. Nature Medicine, September 1999

7 Organ Distribution of Transport Proteins Lymphocytes MDR1 MRP4 MDR1 MRP1 MRP5 Brain OAT3 OATP1 OATP2 Liver LST1 OAT2 MDR1 OAT3 MRP2 OATP1 MRP3 OCT1 NTCP1 SPGP Kidney MDR1 OATP1 MRP1 OATP2 NTCP1 OCT1 OAT1 OCT2 OAT3

8 Pharmacokinetic profile of a single PI administered twice daily and efavirenz given once daily Plasma Concentration Area of Potential Replication EFV PI IC Time (h)

9 NV Study Selection of Doses Peak reduction in HIV-1 RNA (log 10 copies/ml) Fortovase 400 mg tid Fortovase 800 mg tid Fortovase 1200 mg tid ,000 40,000 60,000 80,000 AUC 0 24h (µg.h.l -1 )

10 Relationship between peak reduction in plasma HIV RNA and SQV AUC 0-24h for hard and soft gel formulations Peak reduction in HIV-1 RNA (log 10 copies/ml) Hard gel Soft gel EC 50 = 3226 µg.h.l -1 E max = log 10 copies/ml ,000 40,000 60,000 80,000 AUC 0 24h (µg.h.l -1 ) Gieschke et al., 1999

11 Target Concentration Exposure target of approximately 20,000 µg.h.l -1 with maximal virological response. Target exposure may differ depending on concomitant therapy and patient population. Exposure-response modelling gave the optimal dose of SQV sgc of 1200 mg tid.

12 VIRADAPT Design Retrospective analysis 81 subjects; all received PI in salvage regimen At least 3 samples available for analysis Results Negative correlation between drug concentration and VL Patients subdivided: Optimal Concentration Suboptimal Concentration C trough >IC 50 on C trough <IC 50 on 2 or more occasions 2 or more occasions log at 48 weeks log at 48 weeks

13 Arguments for TDM of PIs Low plasma concentrations correlate with clinical failure Marked inter-individual variability in plasma drug concentrations Complex drug interactions High plasma concentrations may correlate with toxicity PI disposition affected by liver dysfunction Assessment of poor adherence in selected patients Cost of therapy

14 Potential Problems with TDM Relatively small data sets giving concentration-response relationships Target PI concentrations largely defined from in vitro studies with exposure to single PI? Antiretrovirals in combination Changing patterns of adherence What measure is best? AUC Trough Trough and peak

15 Indinavir tds vs bd dosing 100 Plasma Indinavir (µg/ml) µg/ml (100 ng/ml) Time (h)

16 Effect of ritonavir (100 mg) on indinavir pharmacokinetics 100 IND (n=6) IND mg RIT Plasma Indinavir (µg/ml) Time (h)

17 ABT Plasma ABT-378 (µg/ml) Alone + 50 mg RIT EC 50 (WT, 50% HS) Time (h) Sham et al., 1998

18 Efavirenz (SUSTIVA, STOCRIN ) Cl F 3 C C O C N H O

19 Efavirenz Summary of Pharmacokinetics Good oral absorption; can be given without regard to food Half-life h; allows once daily dosing Highly protein bound (99.5%), but penetrates CSF Metabolised by CYP3A4 (also CYP2B6) Induces CYP3A4 (also autoinduction) Inhibits CYP3A4 Renal excretion as glucuronide conjugate

20 Efavirenz Mean Plasma Concentration EFV Plasma Concentration (µm) Time (h) AUC 0-t = 248 µmol.l -1.h C max = 15.7 µmol.l -1 t 1/2 ~ 50 h

21 Efavirenz Free Plasma Concentration EFV Plasma Concentration (nm) Protein Binding = 99.5% IC 95 of WT & clinical isolates = nm Time (h) IC 95 of K103N IC 95 of WT

22 Pharmacokinetic-Surrogate Relationship Plasma Concentration C max AUIC = AUC/MIC MIC T > MIC Time

23 Population Pharmacokinetics of Efavirenz Predicted 24 h EFV plasma concentration (µm) Non-Failure Failure Probability of Success Predicted 24 h EFV plasma concentration (µm)

24 Efavirenz Induction & Inhibition CYP3A4 INDUCED SQV EFV SQV EFV