icon_folder.gif   Conference Reports for NATAP  
 
  ICAAC 41st Interscience Conference on Antimicrobial Agents and Chemotherapy
 
Chicago, Illinois, December 16-19
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Antiviral PK and Drug-Drug Interactions, Report #1
 
Reported for NATAP by Scott Penzak, PhD, National Institutes of Health (NIH)
 
  Subject Index:
1. DdI-allopurinol (gout drug)
2. Ritonavir-antipsychotic medication olanzapine
3. Methadone-ritonavir/saquinavir (1600/100 once daily)
4. Nelfinavir-LAAM/methadone
5. Methadone-delavirdine
6. Indinavir-grapefruit & orange juice
7. Amprenavir/ritonavir once & twice daily in plasma & intracellular
8. Ritonavir/saquinavir & efavirenz
 
Several pharmacokinetic drug interactions involving antiretroviral (ARV) medications were reported at this year's ICAAC in Chicago (Poster Session 47 A/H; Sunday December 16, 3:00 - 4:00 pm). Liang and colleagues evaluated the influence of allopurinol (a xanthine oxidase inhibitor for the treatment of gout) on the pharmacokinetics of didanosine (ddI) -administered as the buffered chewable tablet formulation- in 7 HIV-infected patients.1 Subjects received a single oral dose of ddI (4 X 100 mg tablets) before and after 7 days of allopurinol administration. Allopurinol resulted in a 2.3 fold increase in the ddI area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax). The exact mechanism by which allopurinol increased ddI absorption is unknown but may be related to impaired presystemic biotransformation of ddI due to xanthine oxidase inhibition by allopurinol. Theoretically, this interaction may be virologically beneficial if one assumes that active (triphosphorylated) intracellular concentrations of the drug are proportionately elevated. However, the potential for increased ddI toxicity (peripheral neuropathy; pancreatitis) with concurrent allopurinol may be of greater clinical concern. Areas of continued interest with this combination are the influence of allopurinol on ddI absorption and disposition with repeated ddI dosing and most importantly, the influence of allopurinol on the pharmacokinetics of didanosine enteric-coated preparation.
 
Based upon their cytochrome P450 (CYP) metabolic pathways, there has been considerable speculation over the past several years regarding potential drug interactions between ARV and antipsychotic medications. However, until now, no pharmacokinetic studies had been conducted to confirm or refute such speculation. Investigators reported that ritonavir (dose-escalated to 500 mg twice daily over 11 days) decreased the AUC of a single-dose of olanzapine 10 mg by 53% in 14 HIV-negative healthy volunteers.2 Apparent oral clearance of olanzapine increased by 116% with ritonavir. The likely mechanism of this interaction is induction of olanzapine metabolism through CYP1A2 and glucuronosyl tranferases by ritonavir. Because there is not a well-defined relationship between olanzapine plasma concentrations and therapeutic effect, the clinical implications of this interaction are not entirely clear. Nonetheless, the large magnitude of this interaction suggests that HIV-infected patients receiving this combination may ultimately require higher olanzapine doses to achieve the desired therapeutic effect of the drug. However, it must be noted that the ritonavir dose used in this study (500 mg twice daily) exceeds that commonly used in clinical practice (100-400 mg twice daily as a pharmacokinetic enhancer). While lower doses of ritonavir in combination with other protease inhibitors (e.g. lopinavir; indinavir; amprenavir) might also be expected to lower olanzapine concentrations, it is unclear whether the magnitude of the interaction will be as substantial as that observed in this study.
 
Interactions between ARVs and methadone were the subject of 3 abstracts this year.3,4,6 Shelton and colleagues examined the interaction between methadone and a once-daily saquinavir-ritonavir (1600 mg-100 mg) regimen in 12 HIV-negative volunteers on stable methadone regimens.3 Saquinavir-ritonavir dosing was directly observed and lasted 14 days. Unbound R-methadone (the pharmacologically active form of the drug) was insignificantly reduced by app roximately 8% with saquinavir-ritonavir. The extent of this interaction is not likely to be of clinical significance. Importantly, this study analyzed unbound R-methadone concentrations. Investigations often report R and S total (bound + unbound) methadone concentrations, and this can make their results difficult to assess for clinical significance. An interesting caveat to this study was that the authors also measured saquinavir concentrations and found them to be lower compared to concentrations achieved in other uninfected populations receiving the same regimen. However, the saquinavir Cmin in this study (0.12 [0.05-0.2]) was comparable to that achieved with traditional (thrice daily) saquinavir regimens. Also, the saquinavir AUC-24 in this study (27.7 mcg*hr/mL [20-39]) was greater compared to historical data with thrice daily regimens (12.5 mcg*hr/mL). Further study is necessary to determine whether the once daily saquinavir-ritonavir combination used in this study, produces desirable pharmacokinetics in patients with HIV infection.
 
P.F. Smith and colleagues examined the effect of methadone and the opiate agonist LAAM on the pharmacokinetics of nelfinavir and its pharmacologically active M8 metabolite.4 Healthy non-HIV-infected volunteers maintained on stable doses of either methadone (n=16) or LAAM (n=13) and non-opiate-dependent controls (n=15) received nelfinavir 1250 twice daily for 5 days followed by pharmacokinetic sampling for nelfinavir and M8. Nelfinavir pharmacokinetic parameter values did not differ between the groups, although the median nelfinavir 12-hour trough was higher in methadone recipients compared to control (3.3 vs. 1.2 mM; p< .05). The M8 AUC however, was lower with methadone (9.5 ÁM/mL*h) and higher with LAAM (25.2 ÁM/mL*h) compared to control (18 ÁM/mL*h). Because multiple CYP enzymatic pathways metabolize nelfinavir, and M8 is formed and biotransformed by CYP enzymes, it is difficult to tell which CYP isoform(s) methadone and/or LAAM interacted with to produce their respective effects on nelfinavir and M8 disposition. It is also difficult to determine the potential clinical significance (if any) of these interactions. Because M8 has demonstrated equal potency to nelfinavir against HIV in vitro, the authors speculate that the interaction between methadone and nelfinavir may be of clinical relevance. However, data from a retrospective investigation presented elsewhere at this conference suggests that nelfinavir in combination with methadone is safe and effective in patients co-infected with HIV and Hep-C.5
 
In the last of the methadone interaction studies, the pharmacokinetics of delavirdine and its N-delavirdine metabolite were unaffected by methadone administration in 16 healthy HIV-negative volunteers maintained on methadone compared to 15 non-opiod-dependent controls.6 The influence of delavirdine on methadone disposition was not evaluated
 
Several years ago the manufacturer of indinavir conducted a study in which grapefruit juice administration reduced plasma concentrations of indinavir (administered as a single 400 mg dose) by 26%;7 results from this study were subsequently included in DHHS guidelines for the treatment of HIV infection in adults. Two subsequent studies8,9, including one presented at this poster session9, have shown that grapefruit juice does not alter steady-state plasma concentrations of indinavir. Investigators administered grapefruit juice, Seville orange juice (a known CYP3A4-inhibiting citrus juice) and water along with indinavir to 13 healthy non-HIV-infected volunteers. Other than a delay in indinavir absorption with Seville orange juice, indinavir pharmacokinetic parameter values were unaffected. Results from this study suggest that interpatient variability in indinavir absorption and disposition does not arise from presystemic intestinal metabolism of the drug (since indinavir concentrations were not significantly altered when intestinal CYP3A4 was inhibited by citrus juices). The two take-home points from this study are that (1) interpatient variability in indinavir pharmacokinetics likely arises from variability in meal consumption with the drug, adherence, and hepatic CYP metabolism (2) Grapefruit juice does not alter steady-state pharmacokinetics of indinavir including Cmin, which has been associated with virologic response.
 
Garraffo and coworkers investigated the influence of concurrent ritonavir on plasma and intracellular (IC) amprenavir concentrations in 10 HIV-infected subjects.10 Subjects received amprenavir 1200 mg twice daily, amprenavir 600 mg + ritonavir 100 mg twice daily, and amprenavir 1200 mg + ritonavir 200 mg once daily for a minimum of 10 days. IC amprenavir concentrations were measured pre-dose, 2, and 22 hours (only for the once daily regimen) after dosing. As expected, plasma concentrations of amprenavir were markedly elevated by ritonavir. Cmin was 7-fold higher with amprenavir 600 mg + ritonavir 100 mg twice daily, and 4 fold higher with amprenavir 1200 mg + ritonavir 200 mg once daily, compared to amprenavir 1200 mg twice daily. Amprenavir Cmax and Tmax were unaffected by ritonavir. Of note, Cmin values with all amprenavir regimens were above typical IC50 values of amprenavir against HIV from multiple PI failure patients.11 The geometric mean ratio at Cmin of IC amprenavir: plasma amprenavir was highest (3.52) for the once daily amprenavir-ritonavir regimen, followed by the amprenavir-ritonavir twice daily regimen (2.47); IC amprenavir concentrations were below the limit of quantitation for the amprenavir 1200 mg twice daily regimen. Increased concentrations of IC amprenavir with ritonavir may be due to cellular inhibition of the MDR-1 transporter P-glycoprotein by ritonavir; induction of an influx mechanism by ritonavir is also possible since amprenavir IC:Plasma ratios exceeded 1.0 with concurrent ritonavir. Results from this study provide further support for the feasibility for once daily dosing with an amprenavir-ritonavir combination. This combination has a desirable pharmacokinetic profile and a reduced pill burden that may improve compliance with amprenavir. Also, it is encouraging that intracellular concentrations were highest with the once-daily amprenavir-ritonavir regimen; however, the clinical significance of intracellular protease inhibitor concentrations is not entirely clear and continues to be a focus of debate among pharmacologists.
 
Lastly, Piliero et. al. reported on the pharmacokinetics of saquinavir-ritonavir with and without concurrent efavirenz.12 Twelve non-HIV-infected healthy subjects received saquinavir-ritonavir (400 mg each) twice daily for 10 days (days 1-10) followed by the combination of saquinavir-ritonavir plus efavirenz (600 mg daily) on days 10-24. Pharmacokinetic sampling for saquinavir was done on days 10 (without efavirenz) and 24 (with efavirenz). The (arithmetic?) mean Cmin day 24:day 10 ratio was 0.91; however the standard deviation (0.46) was large. AUC ratios of saquinavir on days 10 and 24 were not reported. Efavirenz Cmin concentrations, measured on day 24, were in agreement with historical data. The authors analyzed the likelihood of free saquinavir Cmin concentrations (defined as 10% of plasma Cmin) exceeding various EC95 concentrations; they found no significant difference after the addition of efavirenz. Results from this investigation are consistent with previous pharmacokinetic data with saquinavir-ritonavir-efavirenz13, both suggesting that efavirenz does not appreciably reduce saquinavir exposure when administered as saquinavir-ritonavir 400 mg twice daily.
 
References
1. Liang D, Breeaux K, Rodriguez M et. al. Allopurinol increases didanosine (ddI) absorption in HIV-infected patients. In: Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL, USA. December 16-19, 2001 [A-498].
 
2. Penzak SR, Lawhorn WD, Hon YY et. al. influence of ritonavir and CYP1A2 genotype on olanzapine disposition in healthy subjects. In: Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL, USA. December 16-19, 2001 [A-493].
 
3. Shelton MJ, Cloen D, Bereson C et. al. Pharmacokinetics (PK) of once daily (QD) saquinavir/saquinavir (SQV/RTV): Effects on unbound methadone and alpha 1-acid glycoprotein (AAG). In: Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL, USA. December 16-19, 2001 [A-492].
 
4. Smith PF, Booker BM, Difrancesco R et. al. Effect of methadone or LAAM on the pharmacokinetics of nelfinavir and M8. In: Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL, USA. December 16-19, 2001 [A-491].
 
5. Brown LS, Chu M, Aug C et. al. The use of nelfinavir and twi nucleosides concomitantly with methadone is effective and well-tolerated in HepC co-infected patients. In: Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL, USA. December 16-19, 2001 [I-206].
 
6. Booker B, Smith P, Forrest A et. al. Lack of effect of methadone (MET) on pharmacokinetics (PK) of delavirdine (DLV) and N-delavirdine (NDLV). In: Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL, USA. December 16-19, 2001 [A-490]. 7. Merck and Company. Crixivan (indinavir sulfate) package insert. West point PA, 1998.
 
8. Shelton MJ, Wynn HE, Hewitt RG, DiFrancesco R. Effects of grapefruit juice on pharmacokinetic exposure to indinavir in HIV-positive subjects. J Clin Pharmacol 2001;41:435-42.
 
9. Effect of Seville orange juice (SOJ) and grapefruit juice (GFJ) on indina vir (IDV) pharmacokinetics (PK) in healthy volunteers. In: Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL, USA. December 16-19, 2001 [A-488].
 
10. Garraffo R, Demarles D, Durant J et. al. Amprenavir (APV) plasma and intracellular concentrations whencoadministered with ritonavir (RTV) in twice and once daily regimen in HIV-1 infected patients. In: Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL, USA. December 16-19, 2001 [A-489].
 
11. Sadler BM, Piliero PJ, Preston SL et. al. Pharmacokinetic drug interaction between amprenavir (APV) and ritonavir (RTV) in HIV-seronegative subjects after multiple, oral dosing. Presented at the 7th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, USA, February 2000 [Abstract 77].
 
12. Piliero PJ, Preston SL, Japour A et. al. Pharmacokinetics of the combination of ritonavir (RTV) plus saquinavir (SQV), with and without efavirenz (EFZ), in healthy volunteers. In: Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL, USA. December 16-19, 2001 [A-495].
 
13. Hendrix CW et. al. Pharmacokinetics of the triple combination of saquinavir, ritonavir, and efavirenz in HIV positive patients. Presented at the 7th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, USA, February 2000 [Abstract 79].