Serum Concentrations of the Antimycobacterial Drugs

Abstract

Therapeutic drug monitoring (TDM) is the process of adjusting drug dosages based on serum concentration data.1Peloquin CA. Using therapeutic drug monitoring to dose the antimycobacterial drugs.Clin Chest Med. 1997; 18: 79-87Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar TDM, or applied pharmacokinetics, allows clinicians to quantify the relationships among drug doses, serum concentrations, therapeutic responses, and concentration-related adverse events.1Peloquin CA. Using therapeutic drug monitoring to dose the antimycobacterial drugs.Clin Chest Med. 1997; 18: 79-87Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar TDM has been applied successfully in the dosing of theophylline, digoxin, gentamicin, and a host of other drugs.2Evans WE. General principles of applied pharmacokinetics.in: Evans WE Schentag JJ Jusko WJ 3rd ed. Applied pharmacokinetics: principles of therapeutic drug monitoring. Applied Therapeutics, Spokane, Wash1992: 1.1-1.8Google Scholar Its use in the dosing of the antimycobacterial drugs is relatively new, and under continuing study. This editorial will address some of the circumstances where the antimycobacterial drug TDM appears to be useful, and some details regarding successful TDM services. Optimal use of TDM requires a complete model of the serum concentration-response curve for a drug. These curves are only partially described for the antimycobacterial drugs.1Peloquin CA. Using therapeutic drug monitoring to dose the antimycobacterial drugs.Clin Chest Med. 1997; 18: 79-87Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar,3Peloquin CA. Pharmacology of the antimycobacterial drugs.Med Clin North Am. 1993; 77: 1253-1262Crossref PubMed Scopus (59) Google Scholar,4Peloquin CA. Mycobacterium avium complex infection: pharmacokinetic and pharmacodynamic considerations that may improve clinical outcomes.Clin Pharmacokinet. 1997; 32: 132-144Crossref PubMed Scopus (25) Google Scholar We do know that if patients fail to take the drugs (serum concentrations of zero), they will fail treatment. We also know that if they absorb isoniazid and rifampin normally, they are very likely to respond to treatment. Somewhere between the “normal” serum concentrations and zero, the activities of isoniazid and rifampin wane.1Peloquin CA. Using therapeutic drug monitoring to dose the antimycobacterial drugs.Clin Chest Med. 1997; 18: 79-87Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar,4Peloquin CA. Mycobacterium avium complex infection: pharmacokinetic and pharmacodynamic considerations that may improve clinical outcomes.Clin Pharmacokinet. 1997; 32: 132-144Crossref PubMed Scopus (25) Google Scholar, 5Comstock GW Hammes LM Pio A. Isoniazid prophylaxis in Alaskan boarding schools: a comparison of two doses.Am Rev Respir Dis. 1969; 100: 773-779PubMed Google Scholar, 6Long MW Snider Jr., DE Farer LS. U.S. Public Health Service cooperative trial of three rifampin-isoniazid regimens in treatment of pulmonary tuberculosis.Am Rev Respir Dis. 1979; 119: 879-894PubMed Google Scholar, 7Donald PR Sirgel FA Botha FJ. The early bactericidal activity of isoniazid related to its dose size in pulmonary tuberculosis.Am J Respir Crit Care Med. 1997; 156: 895-900Crossref PubMed Scopus (118) Google Scholar It appears that this drop-off in activity occurs even more rapidly for ethambutol and the “second-line” antituberculosis drugs. This is not surprising, given the small separation between achievable serum concentrations of those drugs and the concentrations required for them to inhibit or kill mycobacteria.8Doster B Murray FJ Newman R et al.Ethambutol in the initial treatment of pulmonary tuberculosis.Am Rev Respir Dis. 1973; 107: 177-190PubMed Google Scholar Further complicating the relationships between serum drug concentrations and response is the fact that antituberculosis drug therapy appears to have two distinct phases. First, there is the rapid elimination of actively multiplying mycobacteria, known as the early bactericidal activity; and second, there is the slow elimination of semidormant organisms, and those in less accessible areas, known as the sterilizing activity.9Heifets LB. Introduction drug susceptibility tests and the clinical outcome of chemotherapy.in: Heifets LB Drug susceptibility in the chemotherapy of mycobacterial infections. CRC Press, Boca Raton, Fla1991: 13-58Google Scholar It is quite possible that the characteristics of a drug that are important for one phase may be less important during the subsequent phase. Thus, while high maximum serum concentrations relative to the minimal inhibitory concentrations (Cmax/MIC ratios) appear desirable early on, they may be less critical later on. During the sterilization phase, it may be the ability of a drug to remain at the site of infection for long periods of time, and its ability to quickly inhibit or kill mycobacteria, that become more critical. Unfortunately, even if general correlations are established for each drug and phase of treatment, it will be very difficult to know precisely what is occurring inside a particular patient. Several reports have shown altered pharmacokinetic profiles for the antimycobacterial drugs in selected patient groups.1Peloquin CA. Using therapeutic drug monitoring to dose the antimycobacterial drugs.Clin Chest Med. 1997; 18: 79-87Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar Of greatest concern is the frequency with which AIDS patients display low serum concentrations of the antimycobacterial drugs.1Peloquin CA. Using therapeutic drug monitoring to dose the antimycobacterial drugs.Clin Chest Med. 1997; 18: 79-87Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar,10Sahai J Gallicano K Swick L et al.Reduced plasma concentrations of antituberculosis drugs in patients with HIV infection.Ann Intern Med. 1997; 127: 289-293Crossref PubMed Scopus (149) Google Scholar This malabsorption also appears to occur in patients with altered GI tracts, including patients with diabetes mellitus and cystic fibrosis. The latter group is increasingly diagnosed with pulmonary Mycobacterium avium complex (MAC) infection, and drug absorption appears to be a clinically relevant issue.11Larsson LO Berning SE Peloquin CA. Is monitoring of drug therapy in patients with cystic fibrosis and mycobacterial disease necessary [abstract]?.Am J Respir Crit Care Med. 1997; 155: A642Crossref PubMed Scopus (70) Google Scholar In this issue of CHEST (see page 1178), Kimerling and coworkers describe their experience using TDM for the antituberculosis drugs in non-HIV-infected patients. They show that certain patients appear to have difficulty absorbing these drugs. The authors identified these patients based on poor clinical response, which is a useful technique when patients lack the disease states associated with poor drug absorption. The findings of Kimerling et al, along with ours and those of Turner et al,12Turner M McGowan C Nardell E et al.Serum drug levels in tuberculosis patients [abstract].Am J Respir Crit Care Med. 1994; 149: A527Crossref Scopus (80) Google Scholar suggest that drug malabsorption is one of several reasons why 2 to 5% of compliant tuberculosis patients either fail drug therapy or relapse after therapy. TDM appears to be a useful tool for identifying these patients early on, and for adjusting their doses before drug resistance and/or clinical failure occurs. Under these circumstances, TDM can be very cost effective, because it may prevent the need for lengthy and expensive retreatments, and it may prevent additional cases of tuberculosis that occur before treatment failures or relapses are identified. While several case reports have demonstrated these capabilities, the degree to which TDM serves these functions has not been determined in prospective clinical trials. It is clear that TDM is not a substitute for directly observed therapy (DOT). Also, TDM is not a particularly good tool for identifying noncompliant patients. If noncompliance is suspected, such patients require an effective DOT program, that is, one in which a responsible individual verifies that the patient has swallowed the drug doses. TDM does not guarantee successful treatment, but it does eliminate drug malabsorption as a cause of treatment failure. TDM can be particularly effective in guiding therapy with the second-line drugs, when one is trying to balance effective dosing against dose-related toxicities. Serum concentrations inform the clinician on the need to push the doses, especially in the face of a slow response to treatment. When low serum concentrations are documented with standard drug doses, higher doses are required, even if they exceed the so-called “maximum” doses.13American Thoracic Society/American Academy of Pediatrics/Centers for Disease Contro/Infectious Disease Society of America1990 joint statement: diagnostic standards and classification of tuberculosis.Am Rev Respir Dis. 1990; 142: 725-735Crossref PubMed Scopus (412) Google Scholar The true maximum dose is the highest dose that a patient can tolerate, hopefully while achieving the desired therapeutic response. Serious dose-related toxicities are relatively uncommon with the antituberculosis drugs, with the exceptions of cycloserine, and, under conditions such as renal failure, with ethambutol, streptomycin, and the other aminoglycosides. Our experience clearly shows that higher daily doses (>600 mg) of rifampin do not produce the flu-like symptoms, provided that serum concentrations stay within the target range of 8–24 μg/mL; this also appears to be true with twice weekly regimens. Finally, TDM is an excellent tool for adjusting doses in response to drug interactions, which are common in patients with AIDS.1Peloquin CA. Using therapeutic drug monitoring to dose the antimycobacterial drugs.Clin Chest Med. 1997; 18: 79-87Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar TDM services should use sensitive assays that remain specific for the drug of interest even in the presence of multiple other medications. These assays should be extensively validated, and should conform to the guidelines set forth by the College of American Pathologists.14Shah VP Midha KK Dighe S et al.Analytical methods validation: bioavailability, bioequivalence, and pharmacokinetic studies.J Pharm Sci. 1992; 81: 309-312Abstract Full Text PDF Scopus (933) Google Scholar The exact times of doses and blood draws must be recorded. Interpretation of the results are best provided by those familiar with pharmacokinetic principles and the clinical management of patients with mycobacterial infections. If carefully performed and selectively applied, TDM is a powerful tool for optimizing drug therapy in patients with difficultto-treat mycobacterial infections.