Therapeutic Drug Monitoring

Gene D. Morse, Pharm.D., BCPS, FCCP Associate Dean, Clinical Education and Research Professor and Chair, Department of Pharmacy Practice School of Pharmacy and Pharmaceutical Sciences University at Buffalo E-mail: emorse@buffalo.edu Concepta A. Merry, Ph.D., M.S. National Pharmacoeconomics Center, St. James Hospital Dublin, Ireland E-mail: Not Available Judianne C. Slish, Pharm.D. Clinical Assistant Professor Department of Pharmacy Practice University at Buffalo ECMC - Department of Medicine Division of Infectious Diseases 315 Cooke Hall, Buffalo NY, 14260 E-mail: slish@buffalo.edu

Theraputic Drug Monitoring Therapeutic Drug Monitoring (TDM)

Therapeutic Drug Monitoring (TDM) for Antiretrovirals (ARV):

The increasing interest in applying TDM to antiretroviral therapy is related to the observed inter-individual variation in antiretroviral pharmacokinetics that results in a wide range of drug exposure from fixed-dosing regimens and the rapid evolution in the availability of phenotypic assays that generate a target inhibitory concentration (e.g., IC₅₀) as a basis for adjusting individual ARV dosages. Interwoven in the interest in TDM are the complex drug interactions that may result in negative interactions (e.g., lower plasma ARV AUCs). Recently, data have been presented at the 8^th CROI (Chicago, 2001) and at the 2^nd International Workshop on Clinical Pharmacology of HIV Therapy (Noordwijk, 2001) that provide conflicting results with regard to the current role for TDM as a clinical tool (see table below). However, well-designed clinical trials of TDM to examine its potential impact on optimizing chronic ARV therapy are encouraged. Underlying the ability to design trials to examine the potential benefit of TDM are the pharmacologic principals that dictate individual drug exposure during chronic ARV.

Cytochrome p450

Of the predominant human drug metabolizing enzymes (CYP1A2, -2A6, -2B6, -2C9, 2C19,- 2D6, -3A and 2E1), CYP3A accounts for a majority of drug metabolism for commonly used agents^1,2. The CYP3A subfamily of oxidative enzymes consists of CYP3A4, CYP3A5 and CYP3A7³. CYP3A7 is predominantly expressed in fetal life. While 3A4 and 3A5 are both capable of metabolizing 3A substrates, 3A4 is inducible while 3A5 is not susceptible to induction. Recent work has suggested that both 3A4 and 3A5 have clinically relevant isoforms in humans, though the relative importance of 3A4 vs 3A5 remains to be clarified^4,5. CYP3A is found in hepatocytes and in gastrointestinal epithelium. CYP3A5 is expressed in 20-30% of Caucasians and 40-50% of African-Americans⁹⁵. While the exact contribution of 3A5 activity to overall 3A metabolism remains uncertain, genetic variation among individuals may contribute to the considerable range in ARV exposure noted for NNRTIs and PIs.

Antiretroviral Pharmacokinetics and Pharmacodynamics

NRTIs: In general the NRTIs are relatively well absorbed, have minimal plasma protein binding and are either glucuronidated or renally excreted unchanged. Important exceptions include the acid-labile nature of didanosine and the minor P450-mediated metabolism of zidovudine to aminothymidine. However, all of the NRTIs do require sequential intracellular phosphorylation to the active tri-phosphate moiety, a factor contributing to the difficulty is designing a TDM trials with this groups of AVRs.

NNRTIs: Delavirdine has capacity-limited (saturable) hepatic metabolism via CYP 3A (minor clearance via 2D6) and is highly bound to plasma proteins. On the other hand, efavirenz and nevirapine have variable protein binding (efavirenz >98%, nevirapine~60%), but both nevirapine and efavirenz are substrates for CYP3A and are capable of inducing CYP3A activity.

Protease Inhibitors: The PIs are highly bound to plasma proteins (>90%) except for indinavir at 60%. Nelfinavir is the only PI with an active antiviral metabolite (M8), although its relative contribution to overall antiviral activity following nelfinavir administration remains under investigation. The PIs have complex effects on cytochrome p450 activity with indinavir, saqinavir, amprenavir, ritonavir and lopinavir serving as substrates for 3A, while nelfinavir is metabolized by 2C9 and 2C19, with the M8 metabolite further biotransformed via CYP3A. Ritonavir inhibition is broad and includes multiple isoforms with the inhibition being "mechanism-based" and thus not readily reversible. Amprenavir, ritonavir, nelfinavir and lopinavir also induce CYP450 activity during continued administration. Furthermore, recent pharmacokinetic data indicate that dual PI, ritonavir-boosted salvage regimens may provide insufficient drug exposure secondary to these induction effects.

Genetic Factors Influencing ARV Pharmacology

The NNRTIs and PIs have complex pharmacologic characteristics which when understood can be combined to develop potent 3-4 drug regimens. However, the central role of gastric pH, intestinal P-glycoprotein and cytochrome p 450 and hepatic cytochrome p450 activity on the overall drug exposure (as measured by the plasma AUC) from a given ARV make predicting the outcome of complex interactions in clinical practice difficult. Attempts to understand genetic contributions to allow a greater understanding of pharmacokinetic characteristic and pharmacodynamic responses or to predict the net outcome from multiple drug interactions is in early stages. Although p4503A activity is unimodal in the population, contributions from environmental, social and disease factors lead to considerable interpatient variation in individual ARV exposure following fixed-dose administration^6,7.

Antiretroviral Plasma Concentrations, Pharmacodynamics and TDM Studies:

Recent data in support of the role of TDM have primarily been presented in abstract form at scientific meetings and are summarized below:

The compilation of data from the studies in the table above indicates that there is a general trend observed in the reports describing the relationship between plasma concentration of NNRTI and PI and outcome. However, only a few trials (Pharmadapt Athena) have attempted to use TDM as a tool of adjusting individual dosages within a patient. Another concern has been the study design for these types of studies (e.g., Pharmadapt³⁷). These reports also provide documentation that a well-coordinated Pharmacology Laboratory can receive and analyze samples, and provide timely dosage recommendations in support for TDM studies.

Analytical Requirements for Optimal Drug Interactions Assessment Using TDM

The initial use of NRTIs was evaluated with HPLC assays followed by the development of immunoassays⁴⁴. However, TDM for NRTIs has developed slowly due to the lack of time-efficient assays for measuring the intracellular tri-phosphate forms of NRTIs. With the introduction of NNRTIs, HPLC assays continued to be the primary method for quantitating these ARVs. The concurrent introduction of protease inhibitors was accompanied by the continued use of HPLC, but the initial use of LC-MS methods was employed. With the evolution in ARV treatment regimens toward combination therapy the desire to develop a single assay that could accurately quantitate multiple drugs was pursued. Methods for simultaneous assay of four PIs has been presented⁴⁵ and more recently an HPLC method able to measure five PIs and efavirenz was reported⁴⁶.

References

1. de Wildt SN, Kearns GL, Leeder JS, van den Anker JN. Cytochrome P450 3A: ontogeny and drugdisposition. Clin. Pharmacokinet 1999; 37:485-505.[PubMed]

2. Rendic S, Di Carlo FJ. Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metab. Rev. 1997; 29:413-580.

3. Finta C, Zaphiropoulos PG. The human cytochrome P450 3A locus. Gene evolution by capture of downstream exons. Gene 2000; 260:13-23.[PubMed]

4. Felix CA, Walker AH, Lange BJ, Williams TM, Winick NJ, Cheung NKV, Lovett BD, Nowell PC, Blair IA, Rebbeck TR. Association of CYP3A4 genotype with treatment-related leukemia. Proc Natl Acad Sci 1998; 95:13176-13181.[PubMed]

5. Kuehl P, Zhang J, Lamba L, Assem J, Schuetz M, Watkins J, Daly PB, Wrighton A, Hall SA, Maurel SD, Relling R, Brimer M, Yasuda C, Venkataramanan K, Strom R, Thummel S, Boguski, MS. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nature Genetics 2001; 27: 383-391.[PubMed]

6. Wandel C, Witte JS, Hall JM, Stein CM, Wood AJJ and Wilkinson GR. CYP3A activity in African American and European American men: population differences and functional effect of CYP3A4*1B 5’-promoter region polymorphism. Clinical Pharmacol Therapeutic2000;68:82-91.[PubMed]

7. Rivory LP, Qin H, Clarke SJ, Eris J, Duggin G, Ray E, Trent RJ and Bishop JF. Frequency of cytochrome P450 3A4 variant genotype in transplant population and lack of association with cyclosporin clearance. European Journal Clinical Pharmacol 2000;56:395-398.[PubMed]

8. Seminari E., F. Maggiolo, P. Villani, F. Suter, A. Pan, M. B. Regazzi, C. Tinelli, R. Maserati. Efavirenz, Nelfinavir, and Stavudine Rescue Combination Therapy in HIV-1-Positive Patients Heavily Pretreated with Nucleoside Analogues and Protease Inhibitors. J Acquir Imm Def Syndr 1999; 22:453-460.

9. Fletcher C, Fenton T, Powell C, et al: Pharmacologic Characteristics of Efavirenz and Nelfinavir Associated with Virologic Response in HIV-Infected Children. Program and Abstracts of the 8th Conference on Retroviruses and Opportunistic Infections, Chicago, IL 2001; (Abstract)

10. Landman R, Peytavin G, Lamotte C, Aumaitre H, Trylesinski A, Legag S, et al. Therapeutioc drug monitoring of nelfinavir in a prospective study in HIV-HCV co-infected patients with chronic liver disease. The 2nd International Workshop on Clinical Pharmacology of HIV Therapy. Abs 6.4., April 2-4, 2001

11. Descamps D, Peytavin G, Calvez V, et al: Virologic Failure, Resistance and Plasma Drug Measurements in Induction Maintenance Therapy Trial (072 Trilege). 6th Conference on Retroviruses and Opportunistic Infections 1999; (Abstract

12. Stein D. S., D. G. Fish, J. A. Bilello, S. L. Preston, G. L. Martineau, G. L. Drusano. A 24-week open-label Phase I/II evaluation of the HIV protease inhibitor MK-639 (indinavir). AIDS 1996; 10:485-492.[PubMed]

13. Harris M, Durakovic S, Rae S, Raboud J, Fransen S, Shillington A, Conway B, Montaner J. A pilot study of nevirapine, indinavir, and lamivudine among patients with Advanced human immunodeficiency virus disease who have had failure of combination nucleoside therapy. J Infect Disease 1998;177;1514-1520

14. Murphy R. L., J. P. Sommadossi, M. Lamson, D. B. Hall, M. Myers, A. Dusek. Antiviral effect and pharmacokinetic interaction between nevirapine and indinavir in persons infected with human immunodeficiency virus type 1. J. Infect. Dis. 1999; 179:1116-1123.[PubMed]

15. Acosta E., K. Henry, L. Baken, L. Page, C. V. Fletcher. Indinavir Concentrations and Antiviral Effect. Pharmacotherapy 1999. 19(6):708-712.[PubMed]

16. Acosta EP, Havlir DV, Richman DD, et al: Pharmacodynamics (PD) of Indinavir (IDV) in Protease-Naive HIV-Infected Patients Receiving ZDV and 3TC. 7th Conference on Retroviruses and Opportunistic Infections 2000:(Abstract)

17. Burger DM, Hoetelmans RM, Hugen PW, Mulder JW, Meenhorst PL, Koopmans PP, Brinkman K, Keuter M, Dolmans W and Hekster YA. Low plasma concentrations of indinavir are related to virological treatment failure in HIV-1-infected patients on indinavir-containing triple therapy. Antiviral Therapy 1998;3:215-220.[PubMed]

18. Fletcher C. V., R. C. Brundage, R. P. Remmel, L. M. Page, D. Weller, N. R. Calles, C. Simon, M. W. Kline. Pharmacologic Characteristics of Indinavir, Didanosine, and Stavudine in Human Immunodeficiency Virus-Infected Children Receiving Combination Therapy. Antimicrob. Agent Chemother. 2000; 1029-1034

19. Marzolini C., A. Telenti, G. Decosterd, J. Biollaz, T. Buclin. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1 infected patients. AIDS 2001; 15:71-75.[PubMed]

20. Kempf D, Hsu A, Jiang P, et al: Response to Ritonavir (RTV) Intensification in Indinavir (IDV) Recipients Is Highly Correlated with Virtual Inhibitory Quotient. Program and Abstracts of the 8th Conference on Retroviruses and Opportunistic Infections, Chicago, IL 2001; 523:200(Abstract)

21. Fletcher CV, Anderson P, Kakuda T, et al: A Novel Approach to Integrate Pharmacologic and Virologic Characteristics: An In Vivo Potency (IVP) Index for Antiretroviral Agents. Program and Abstracts of the 8th Conference on Retroviruses and Opportunistic Infections, Chicago, IL 2001; (Abstract)

22. Kakuda T., L. Page, P. Anderson, K. Henry, T. Schacker, F. Rhame, E. Acosta, R. Brundage, C. Fletcher. Pharmacological Basis for Concentration-Controlled Therapy with zidovudine, Lamivudine, and Indinavir. Antimicrob Agent Chemother 2001;45:236-242.

23. Burger D, Felderhof M, Phanupak P, et al: Both Short-Term Virological Efficacy and Drug-Associated Nephrotoxicity are related to Indinavir (IDV) Pharmacokinetics (PK) in HIV-1 Infected Thai Patients. Program and Abstracts of the 8th Conference on Retroviruses and Opportunistic Infections, Chicago, IL 2001; (Abstract)

24. Peytavin G, Lamotte C, Duval X, Matheron S, Boue F, deTruchis P, et al. Amprenavir plasma concentrations are dramatically decreased by the association with ABT378/r in HIV-infected patients. The 2nd International Workshop on Clinical Pharmacology of HIV Therapy. Abs 1.14.,. April 2-4, 2001.

25. Mueller B. U., S. L. Zeichner, V. A. Kuznetsov, M. Heath-Chiozzi, P. A. Pizzo, D. S. Dimitrov. Individual prognoses of long-term responses to antiretroviral treatment based on virological, immunological and pharmacological parameters measured during the first week under therapy. AIDS 1998; Oct.22; 12:F191-F196.[PubMed]

26. Danner S., A. Carr, J. Leonard, L. Lehman, F. Gudiol, J. Gonzales, A. Raventos, R. Rubio, E. Bouza, et al. 1995. A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of hiv-1 protease. New England J Medicine 333:1528-1533.

27. Poirier JM, Meynard JL, Guiard-Schmid JB, Morand-Joubert L, Scheider V, Jacquemet N, et al. Unexpected drug-drug interaction between amprenavir and ritonavir. The 2nd International Workshop on Clinical Pharmacology of HIV Therapy. Abs 1.6.,. April 2-4, 2001.

28. Duval X, Race E, Lamotte C, Descamps D, Gervais A, Breton G, Longuet P, et al. Inhibitory qiotient (IQ) and efficacy of amprenavir (APV)-lopinavir (ABT-r) containing HAART in heavily pretreated HIV infected patients. The 2nd International Workshop on Clinical Pharmacology of HIV Therapy. Abs 5.11., April 2-4, 2001.

29. Schapiro J. M., M. A. Winters, F. Stewart, B. Efron, J. Norris, M. J. Kozal, T. C. Merigan. 1996. The Effect of High-Dose Saquinavir on Viral Load and CD4+ T-Cell Counts in HIV-Infected Patients. Ann. Intern. Med. 124:1039-1050.[PubMed]

30. Hoetelmans RM, Heeswijk RP, Meenhorst VP, et al: Plasma concentrations of saquinavir determine HIV-1 RNA response over a 48-week period. 12th World AIDS Conference Geneva 1998; (Abstract)

31. Hsu et al. Glasgow 2000

32. Kempf D, Hsu A, Isaacson J, Jiang P, Brun S, Renz C et al. Evaluation of the inhibitory quotient as a pharmacodynamic predictor of the virologic response to protease inhibitor therapy.

33. Poirier JM, Meynard JL, Guiard-Schmid JB, Morand-Joubert L, Scheider V, Jacquemet N, et al. Lopinavir and ritonavir trough plasma concentrations in HIV-experienced patients treated with kaletra. The 2nd International Workshop on Clinical Pharmacology of HIV Therapy. Abs 1.7., April 2-4, 2001.

34. Mayers D., Merigan T, Wentworth D, Neaton J, Hoover M, Hoetelmans R, Verbiest W, Baxter J and the CPCRA 046 Study Team. Both antiretroviral drug levels and drug resistance are associated with short-term virologic responses to subsequent drug regimens in CPCRA 046 (GART study). The 2nd International Workshop on Clinical Pharmacology of HIV Therapy. Abst 5.2,. April 2-4, 2001.

35. Durant J., P. Clevenbergh, R. Garraffo, P. Halfon, S. Icard, P. Del Giudice, N. Montagne, J. Schapiro, P. Dellamonica. Importance of protease inhibitor plasma levels in HIV-infected patients treated with genotypic-guided therapy: Pharmacological data from the Viradapt Study. AIDS 2000;14:1333-1339.[PubMed]

36. Clevenbergh P, Durant J, Garraffo R, et al: Usefulness of Protease Inhibitor Therapeutic Drug Monitoring? PharmAdapt: A Prospective Multicenter Randomized Controlled Trial: 12 Weeks Results. Program and Abstracts of the 8th Conference on Retroviruses and Opportunistic Infections, Chicago, IL 2001; (Abstract)

37. Burger DM, Hugen PW, Droste J, Huitema AD, for the Athena Group. Therapeutic drug monitoring of indinavir in treatment-naïve patients improves therapeutic outcome after 1 year: results from ATHENA. The 2nd International Workshop on Clinical Pharmacology of HIV Therapy. Abst 6.2a,. April 2-4, 2001.

38. Burger DM, Hugen PW, Droste J, Huitema AD, for the Athena Group. Therapeutic drug monitoring of nelfinavir in treatment-naïve patients improves therapeutic outcome after 1 year: results from ATHENA. The 2nd International Workshop on Clinical Pharmacology of HIV Therapy. Abst 6.2b,. April 2-4, 2001.

39. Marzolini C, Greub G, Decosterd L, et al: Routine Antiretroviral Plasma Levels of NNRTIs and PIs Correlate with Viral Suppression and Adverse Events. Program and Abstracts of the 8th Conference on Retroviruses and Opportunistic Infections, Chicago, IL 2001; (Abstract)

40. Demeter LM, Meehan PM, Morse G, Fischl M, Para M, Powderly W, Leedom J, Holden-Wiltse J, Wood K, Timpone J Jr, Wathen L, Resnick L, Batts D, Reichman RC. Phase I study of atevirdine mesylate (U-87201E) monotherapy in HIV-1 infected patients. J Acquir Immune Defic Syndr Hum Retrovirol 1998;19(2):135-144.[PubMed]

41. Morse GD, Reichman RC, Fischl MA, Para M, Leedom J, Powderly W, Demeter LM, Resnick L, Bassiakos Y, Timpone J, Cox S, Batts D, and the ACTG 187 and 199 Study Teams. Concentration-targeted phase I trials of atevirdine mesylate in patients with HIV infection: dosage requirements and pharmacokinetic studies. Antiviral Res 2000.45(1)47-58.[PubMed]

42. Para MF, Meehan P, Holden-Wiltse J, Fischl M, Morse G, Wood K, Shafer R, Demeter L, Nevin T, Freimuth WW. ACTG 260: a randomized, phase I-II, dose-ranging trial of the anti-HIV activity of delavirdine monotherapy.The AIDS Clinical Trials Group Protoclo 260 Team. Antimicrob Agent Chemother June 1999 43(6): 1373-78.[PubMed]

43. DeRemer M, D’Ambrosio R, Bartos L, Cousins S, Morse GD. Radioimmunoassay of zidovudine: extended use and potential application. Ther Drug Monit 1997;14(2):195-200.[PubMed]

44. Remmel RP. Kawle SP. Weller D. Fletcher CV. Simultaneous HPLC assay for quantification of indinavir, nelfinavir, ritonavir, and saquinavir in human plasma. Clinical Chemistry 2000 Jan;46(1):73-81.[PubMed]

45. G. Morse*, R. Difrancesco, L. Bartos, and R. Hewitt. Simultaneous Measurement of Five Protease Inhibitors Plus Efavirenz. 8th Conference on Retroviruses and Opportunistic Infections. Chicago, Feb 2001. Abs 733

Back to TOP