The Potential Role of Therapeutic Drug Monitoring in the Treatment ...

Review - Therapeutic Drug Monitoring Volume 10 Issue 2 May/June 2002ReviewThe Potential Role of Therapeutic Drug Monitoring in theTreatment of HIV InfectionJohn G. Gerber, MD, and Edward P. Acosta, PharmDAbstract. Therapeutic drug monitoring (TDM) is increasinglybeing used in clinical practice in order to improve the therapeuticoutcome in HIV infection. The use of TDM requires certainpharmacologic, analytical, and clinical criteria in order tointerpret the plasma concentrations appropriately. In thiscontext, we have reviewed whether there are enough datato recommend the widespread use of TDM in the treatmentof HIV infection. Nucleoside reverse transcriptase inhibitorsare prodrugs that require intracellular metabolism for activity,so as a group they would not qualify for TDM in plasma.Although TDM potentially could be helpful in improving theefficacy and reducing the toxicity of protease inhibitors andnonnucleoside reverse transcriptase inhibitors, without clearlydefined therapeutic ranges for many of these drugs andwith few prospective TDM trials showing efficacy, plasmaTDM has to be considered as an experimental tool in mostclinical settings.Therapeutic drug monitoring (TDM) is defined as a strategy bywhich the dosing regimen for a patient is guided by repeatedmeasurements of plasma drug concentrations. If the concentrationis not within a predefined target range, the dose is adjustedto bring this level within this target range (Figure 1). The 2main reasons to undertake TDM in clinical situations are toavoid drug toxicity and to improve therapeutic efficacy. The historyof TDM in clinical medicine is relatively brief, even thoughthe concept that both efficacy and toxicity of a drug are doseandconcentration-dependent has been well established. Use ofTDM in clinical medicine has been clearly linked to the developmentof assays that are accurate, sensitive, specific, and havea rapid turnaround time.Although TDM is used in the treatment of several diseases,there is very little rigorous scientific evidence that its use hasimproved clinical outcome in patients. 1 The use of TDM in theprevention of drug toxicity has a stronger basis than the use ofTDM for improved efficacy. This should not be surprising sincetherapeutic outcome is multifactorial and includes the importanceof individual drug-taking behavior. For the treatment ofHIV infection, TDM has another layer of complexity: incompleteviral suppression during therapy may result in HIV mutations sothat drug susceptibility may become a moving target. This isquite unique compared with other diseases where TDM hasbeen applied, in which the target concentration range remainsthe same throughout therapy.The use of TDM in the pharmacotherapy of HIV infection isgaining momentum despite the fact that there are no clear-cuttherapeutic ranges established for any of the antiretroviraldrugs. HIV treatment requires the concomitant use of multipledrugs for durable viral suppression; however, TDM usuallyinvolves the monitoring of only a single drug concentration. Theutility of TDM to improve therapeutic outcomes in HIV-infectedpatients has not been definitively demonstrated in large clinicaltrials, and therefore its use should be considered investigational.In this article we will review the criteria required for the useof TDM in clinical medicine and evaluate how antiretroviraldrugs fare in this regard. In addition, we will review data fromthe few prospective clinical trials that have been published orpresented that address the utility of TDM in the management ofHIV infection. Unfortunately, there are no prospective studiesthat have attempted to measure the cost-effectiveness of TDMin the treatment of HIV infection.Drug ConcentrationTimeTherapeuticFailure/ToxicityTherapeuticSuccessTherapeuticFailureFigure 1. The mechanism by which therapeutic concentrations fora drug can be established. The ordinate represents drug concentrationand the abscissa represents a time factor on therapy. The bottomsaw-toothed line shows concentrations where therapeutic failureresults from suboptimal drug concentration. The middle linerepresents the optimal drug concentration for therapeutic success.The top line shows the concentrations that result in therapeutic failuresecondary to toxicity from high drug concentrations.Author Affiliation: John G. Gerber, MD, is Professor of Medicine and Pharmacology in the Divisions of Clinical Pharmacology and InfectiousDiseases at the University of Colorado Health Sciences Center in Denver. Edward P. Acosta, PharmD, is Assistant Professor in the Division ofClinical Pharmacology at the University of Alabama at Birmingham. Received March 8, 2002; accepted May 8, 2002.27

International AIDS Society–USATopics in HIV MedicineTable 1. Characteristics of Antiretroviral Drugs Applicablefor Therapeutic Drug MonitoringCriteriaAnalyticalDrug assay is accurate, specific, precise,requires small sample volume, yieldsrapid results, and is inexpensivePharmacokineticPharmacokinetic data are availableSignificant interpatient pharmacokineticvariability existsPharmacologicPharmacologic effect is related to drugconcentrationDrug has a narrow therapeutic indexDrug has constant pharmacologic effectover extended period of timeClinicalClinical studies have documented thetherapeutic and toxic ranges of the drugCriteria for TDM Use in Clinical MedicineThe required criteria for the use of TDM in clinical medicinewere described by Spector and colleagues in 1988. 2 These criteriaare reviewed below in the context of antiretroviral drugs andcharacteristics that make drugs candidates for TDM (Table 1).Analytical CriteriaEvaluation√ indicates sufficient data are available for antiretroviral drugs tomeet the specified criterion; ± indicates some data are available butthe criterion has not been met. *Depends on the extent of viralinhibition. Adapted from Spector et al, Clin Pharmacol Ther, 1988.A drug assay is available with high specificity, small sample volume requirements,reasonable cost, and rapid turnaround time.Very sensitive and specific assays are available for all the proteaseinhibitors, nonnucleoside reverse transcriptase inhibitors(NNRTIs), and nucleoside reverse transcriptase inhibitors(nRTIs) using high-performance liquid chromatography withultraviolet (HPLC-UV) detection or liquid chromatography-massspectrometry/mass spectrometry (LC-MS/MS). However, nRTIsare more complex than protease inhibitors and NNRTIs sincethey circulate in the plasma as prodrugs and require intracellularphosphorylation to the active triphosphate metabolite. As aresult, plasma concentrations of nRTIs may not always reflectactivity in the intracellular compartment. A good example isdidanosine, which has a very short plasma half-life but a longintracellular half-life and duration of action. 3 Since it has been√√√√±±*±very difficult to measure accurately the intracellular concentrationsof many nRTI triphosphates, nRTIs may not be good candidatesfor TDM and thus will not be included in the discussionof the other criteria for TDM. The analytical criteria required forapplication of TDM is met by the protease inhibitors andNNRTIs; the cost and turnaround time criteria will likely be metas more laboratories undertake the analysis of these drugs.Pharmacokinetic CriteriaThere is significant interindividual variability in pharmacokinetics, resultingin large variability in achieved plasma concentrations. Adequate pharmacokineticdata concerning the drug are available.Although a fixed dose is administered to all adults taking proteaseinhibitors and NNRTIs, large variability in achieved plasmaconcentrations has been well documented for all the drugsin clinical use. 4-7 A number of pharmacokinetic studies havebeen conducted on currently available antiretroviral drugs asreviewed in a recent position paper on TDM. 8 All proteaseinhibitors have large intersubject variability in achieved plasmaconcentration following fixed-dose administration (Figure 2).This variability becomes a concern when the achieved troughconcentration is below the concentration necessary for inhibitionof viral replication, thereby creating the potential for theevolution of drug-resistant isolates. Administration of ritonavirwith other protease inhibitors tends to reduce the pharmacokineticvariability of the protease inhibitors, but the intersubjectvariability still remains high. 9 Large interindividual variability isalso present with achieved plasma concentrations of NNRTIs,yet it is unclear whether failure of NNRTI-based therapy is dueto low plasma concentrations. Achieved plasma concentrationsfor nevirapine are orders of magnitude higher than what isrequired for viral inhibition in vitro. 10 However, quasi specieswith high-level drug resistance circulate as minority strains, andtherefore adequate exposure to concomitant nRTIs is likely crucialin maintaining successful therapy with most of the NNRTIs.Indinavir Concentration (µM)201510500 1 2 3 4 5 6 7 8Time (hours)Figure 2. The extreme variability of the pharmacokinetics of a proteaseinhibitor (indinavir) following standard dosing (800 mg q8h).Similar data showing large intersubject variability in pharmacokineticsare available for other protease inhibitors. Adapted with permissionfrom Acosta et al, Pharmacotherapy, 1999.28

Review - Therapeutic Drug Monitoring Volume 10 Issue 2 May/June 2002There are many reasons behind pharmacokinetic variabilityof these lipophilic drugs. There is undoubtedly variability indrug solubilization and absorption from the intestinal tract.Multidrug-resistant proteins such as P-glycoprotein likelyimpede the bioavailability of protease inhibitors. In addition,the large variability of CYP3A expression in the small intestineand the liver can result in significant variability in the drug'sbioavailability and systemic clearance. Based upon the largeintersubject pharmacokinetic variability of protease inhibitorsand NNRTIs and the sufficient data available on their pharmacokineticprofiles, both drug classes qualify for TDM.Pharmacologic CriteriaPharmacologic effect is proportional to the plasma drug concentration. Anarrow range exists between the efficacious and toxic concentrations. A constantpharmacologic effect over an extended period of time exists.Higher plasma concentrations of protease inhibitors haveresulted in a greater HIV-1 RNA response during initial doserangingstudies as well as in clinical trials. This is not surprisingsince the basic tenet of pharmacology is that a concentrationresponserelationship exists with all clinically active drugs.Under certain circumstances, however, this relationship may notalways hold true. One is the presence of active metabolites thatcan contribute to the overall therapeutic activity of the drug. Ofthe available protease inhibitors and NNRTIs, only nelfinavir isassociated with a measurable active metabolite in the plasma. 11The hydroxylated metabolite is designated as M-8 and is generatedby nelfinavir's oxidation by CYP2C19. 12 M-8 and nelfinavirhave equipotent in vitro activity against HIV. At this point, it isunclear to what extent the M-8 metabolite contributes to theoverall antiretroviral activity after nelfinavir administration. It islikely that M-8 plasma binding is significantly less than nelfinavirplasma binding, so that the fraction of the drug that equilibratesintracellularly may be higher for M-8 than for nelfinavir.More research is required since in clinical use nelfinavir appearsto be more effective than what would be predicted from its plasmaconcentration alone.Protein binding is another factor influencing the concentration-responserelationship for protease inhibitors becausechanges in overall binding of these drugs could affect the waytotal drug concentrations are interpreted. HIV replication occurswithin cells, and protease inhibitors have to reach their intracellulartarget for activity. At equilibrium, the unbound concentrationof a drug in plasma should be equivalent to the unboundconcentration in the cell as long as there are no energy-dependentpumps that can transport drugs against a concentrationgradient. The importance of the unbound concentration of adrug for activity was clearly demonstrated by the lack of clinicalactivity of the protease inhibitor SC-52151. 13 Because of its highdegree of protein binding, the drug showed no activity despiteachieving seemingly adequate plasma concentration based onin vitro anti-HIV activity.Protease inhibitors are organic bases that are mostly boundin plasma to α 1 -acid glycoproteins (AAGs), which are acutephasereactants whose concentrations increase under conditionsof infection and acute inflammation. 14 The extent of proteinbinding of protease inhibitors is dependent upon the concentrationof AAGs. 15 Higher concentrations of AAGs result inincreased protein binding of protease inhibitors. Changes inprotein binding for drugs like indinavir, which is only 60% plasmabound, will not greatly affect plasma-unbound concentrationsand antiretroviral activity. In contrast, changes in proteinbinding for highly protein-bound drugs, such as nelfinavir andlopinavir, will significantly alter their activity at an equivalentplasma concentration. Thus when total plasma concentration ofa highly protein-bound drug is interpreted, the same concentrationwith variable protein binding may not translate into equivalentantiretroviral activity. Nonetheless, there is some evidencethat the pharmacologic effect of protease inhibitors is proportionalto the plasma concentration in drug-naive subjects. 16The treatment of HIV infection requires multiple drugs fordurable efficacy. For NNRTIs, the concentration-response relationshipis less firmly established, but data with efavirenzincreasingly point in that direction. 7 It is presently unclear ifconcomitant use of all the nRTIs will result in an equivalentantiretroviral efficacy at a specific protease inhibitor or NNRTIconcentration. It is this high level of pharmacologic complexityin the treatment of HIV infection that makes the relationshipbetween plasma concentration of protease inhibitors andantiretroviral response difficult to predict.The therapeutic ranges for protease inhibitors and NNRTIsare difficult to evaluate because most drugs cannot be pushedto maximally tolerated doses. There are both absorption andtolerability limitations for these agents. It is likely that mostdrugs used in the treatment of HIV infection have a narrowrange between the tolerated dose and the systemic concentrationrequired for durable suppression. Gatti and colleaguesclearly demonstrated that adverse effects of ritonavir are correlatedto both peak and trough concentrations. 17 The tolerabilityof ritonavir is dose dependent and most patients do not toleratethe usual dose necessary for durable antiretroviral efficacy,600 mg twice daily. Consequently, ritonavir is used mainly as ametabolic inhibitor of other protease inhibitors at a lower andbetter-tolerated dose.For nelfinavir, for which most of the toxicity is gastrointestinal,there is no relationship between plasma concentration andthe development of diarrhea. 18 Nephrotoxicity caused by indinavirhas been related to a peak plasma concentration (C max )above 10 µg/mL. 19 Since indinavir has a very short plasma halflife,a large amount of drug has to be administered to maintainadequate trough concentrations (C trough ). As a result, thepeak/trough ratio for indinavir is the highest among the proteaseinhibitors. The high C max of indinavir can be manipulatedby using lower indinavir doses with low-dose ritonavir to prolongthe drug's plasma half-life. 20For NNRTIs, central nervous system (CNS) toxicity associatedwith efavirenz has been shown to be related to plasma concentration,and the concentration necessary for maximal activityis not far from the concentration that results in CNS toxicity. 7The presence or evolution of resistant viral strains willdetermine whether antiretroviral drugs exhibit a constant pharmacologiceffect over an extended period of time. The HIVreverse transcriptase gene does not contain a “proofreading”mechanism, and as long as the virus is replicating, it can generatemutations that confer reduced susceptibility to antiretroviraldrugs. If viral replication is contained, a constant pharmaco-29

International AIDS Society–USA Topics in HIV Medicinelogic effect over an extended period of time does indeed occurfor both the protease inhibitors and the NNRTIs. If mutated andphenotypically less susceptible viral strains evolve during therapy,the pharmacologic effect is not constant over even a shortperiod of time. Higher concentrations of drugs may need to beachieved to control viral replication to the same extent as duringinitial therapy.Based on these pharmacologic criteria, the applicability ofTDM to antiretroviral drugs is variable. Since treatment of HIVinfection requires the concomitant use of multiple drugs, monitoringonly a single drug (eg, a protease inhibitor or NNRTI)may not be appropriate. Both the therapeutic efficacy and thetoxicity of protease inhibitors and NNRTIs may demonstratesynergy, antagonism, or additive effects when combined withthe various nRTIs or each other. The presence of baseline minoritydrug-resistant mutations and the evolution of drug resistanceover time can make the concentration necessary forantiretroviral efficacy a moving target.Clinical CriteriaClinical studies exist that define the therapeutic and toxic ranges of the drug.A therapeutic range has not been formally defined for all drugsin clinical use for HIV, but concentration-response data areavailable for most of the protease inhibitors and NNRTIs. Oneproblem is the uncertainty as to which pharmacokinetic parameterbest defines the therapeutic and toxic exposures of thedrugs. The C trough is usually monitored to determine adequatedrug exposure because it is the easiest to collect for both thepatient and the investigator; however, this parameter requiresan accurate recall of when the last dose of the drug was administered.Calculating an accurate area-under-the-curve valuewould require obtaining specimens over an extended period oftime, which is unrealistic in a busy clinical setting. Logically,C trough should define the lowest drug concentration during adosage interval and thus define the minimum effective concentrationof the drug, but this has not been prospectively validatedfor any of the antiretroviral drugs.In terms of toxicity, the trough and the peak drug concentrationseach may play an important role. For example, C max maybest approximate the risk of indinavir-induced nephrotoxicity, 19but other toxicities such as skin and nail abnormalities may berelated to total drug exposure. Marzolini and colleaguesattempted to define the therapeutic range of efavirenz by retrospectivelycorrelating CNS toxicity with plasma concentrationsin a small group of subjects, some of whom were experiencingvirologic failure. 7 Although this may be one way to define thetherapeutic ranges for drugs, prospective studies that validatethese drug concentrations with observations of efficacy and toxicitywould certainly strengthen the argument for TDM.In drug-naive subjects, the C trough necessary for continuedviral suppression has been defined best for indinavir. This concentrationis approximately 100 ng/mL, which is close to theprotein-binding-corrected 95% inhibitory concentration for indinavirin vitro. 16 However, the determination of the C trough necessaryfor durable virologic suppression is made in the presenceof concomitant nRTIs, and whether all of the nRTIs interact withthe protease inhibitors at the same potency in vivo has not beenstudied. Abacavir, for example, which is a much more potentantiretroviral drug than stavudine, may quantitatively contributeto successful therapy more than stavudine when usedconcomitantly with protease inhibitors. 21,22Prospective Clinical TrialsThere are only a few prospective studies that have examined theutility of TDM in the treatment of HIV. ATHENA was a prospectivetrial of TDM in which analyses of a subgroup of patients onindinavir or nelfinavir were performed. 23 Ninety-two treatmentnaivepatients were randomized to receive nelfinavir 1250 mgtwice daily using TDM or no TDM. A concentration ratio (CR)was used to assess drug exposure and make dosing modificationsin the TDM group. A measured drug level (drawn at anytime following an unobserved dose) was compared with a populationaverage concentration-time curve. A ratio of 1 meant thepatient’s concentration was the same as the population averageon that occasion. If the first nelfinavir CR was less than 0.9, takingthe drug with food was discussed with the patient. If thesubsequent CR remained less than 0.9, the dose was increasedto 1500 mg twice daily, and low-dose ritonavir was added if thethird CR was low. The average turnaround time for the assayresults was 4 weeks.By intent-to-treat (ITT) analysis, the proportions of patientsachieving plasma HIV-1 RNA levels below 500 copies/mL at 1year were 81% and 59% in the TDM and no-TDM groups, respectively(P=.03). The authors suggested that these results reflecteddifferences in drug efficacy because the main reason for drugdiscontinuation in the no-TDM group was virologic failure,which was more frequent for the no-TDM group.The ATHENA study also examined the effect of TDM in subjectsreceiving indinavir 800 mg 3 times a day, indinavir 800 mgwith 100 mg ritonavir twice daily, or indinavir plus ritonavir at400 mg each twice daily. The acceptable CR for indinavir wasdefined as 0.75 to 2.0. This analysis showed more favorable outcomesin the group randomized to TDM. By ITT analysis, 75%and 48% of subjects had plasma HIV-1 RNA levels below 500copies/mL in the TDM and no-TDM arms, respectively, at 1 year.This difference was secondary to toxicity, since there were veryfew virologic failures and far fewer subjects in the TDM armdropped out of the study for toxicity reasons than those in theno-TDM arm. These data suggest that TDM may be potentiallyuseful in the management of antiretroviral therapy for both efficacyand toxicity reasons. Although these substudies of theATHENA trial had positive results, concerns remain regardingthe statistical power of the study to detect differences betweengroups and whether clinicians truly followed dose change recommendations.PharmAdapt was a prospective study comparing the use ofTDM versus no TDM in treatment-experienced patients in whomtherapy failed. 24,25 A total of 257 subjects enrolled in this study,but the presented data were limited to 180 subjects receivingprotease inhibitor-containing regimens. Ninety-six subjectswere in the control group and 84 subjects were in the TDMgroup. All subjects had genotypic resistance testing prior to randomization,and drug therapy was determined on the basis ofthese results. The TDM group had a dose modification at week8 based on week 4 trough concentrations. The targeted protease30

International AIDS Society–USA Topics in HIV MedicineIn the treatment of drug-experienced subjects who havedrug-resistant virus, determining a protein-corrected IC 50 maybe useful. Applying TDM to then achieve a concentration several-foldabove that IC 50 would seem reasonable. Evaluation of theinhibitory quotient (IQ), in which the phenotypic sensitivity ofthe virus to the drug and the plasma concentration of the drugdetermine the IQ, is being studied in clinical trials. Welldesignedand adequately powered prospective studies need tobe performed before IQ can be generally recommended for clinicalpractice.The important message about TDM is that it may ultimatelyprove useful, but at this time there are not enough data to recommendits use outside of very specific circumstances. TDMshould currently be viewed as an investigational tool to exploremeans of improving therapeutic outcome and reducing toxicitiesin the treatment of HIV infection.Financial Disclosure: Dr Gerber has served as a consultant to Agouron, Merck, RocheDiagnostics, and Roche Pharma. Dr Acosta has served as a consultant to Bristol-MyersSquibb, Merck, and Roche.References1. Schumacher GE, Barr JT. Economic and outcome issues for therapeuticdrug monitoring in medicine. Ther Drug Monit. 1998;20:539-542.2. Spector R, Park GD, Johnson GF, Vesell ES. Therapeutic drug monitoring.Clin Pharmacol Ther. 1988;43:345-353.3. Morse GD, Shelton MJ, O'Donnell AM. Comparative pharmacokinetics ofantiviral nucleoside analogues. Clin Pharmacokinet. 1993;24:101-123.4. Acosta EP, Henry K, Baken L, Page LM, Fletcher CV. Indinavir concentrationsand antiviral effect. Pharmacotherapy. 1999;19:708-712.5. Baede-van Dijk PA, Hugen PW, Verweij-van Wissen CP, Koopmans PP,Burger DM, Hekster YA. 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