Limited-Sampling Strategies for Anti-Infective Agents: DISCUSSION
Study Strengths and Limitations
Six studies of limited-sampling strategies were considered to present evidence of the highest quality (level I), describing strategies for didanosine, zidovudine, nevirapine, ciprofloxacin, efavirenz, and nelfinavir). Each study used prospectively collected data and proper validation procedures. All 6 studies randomized pharmacokinetic data into index and validation groups, and 5 of the studies clearly randomized the pharmacokinetic data into independent data sets. Each study illustrated the potential utility of limited- sampling strategies by requiring only 1 or 2 blood samples to predict AUC, with minimal bias and relatively good precision. The level I studies of didanosine and zidovudine also provided 1-sample limited-sampling strategies to predict a second pharmacokinetic parameter, maximum drug concentration.
Of the level I studies, the study of a validated limited- sampling strategy for nevirapine probably provided the most flexibility and convenience for clinical use. In that study, all 14 sampling data points were used to determine a 1-sample (i.e., a random sample between 2 and 4 h after dosing) limited- sampling strategy that predicted the AUC with minimal bias and good precision. This single “random” sample would be a convenient method for future research to determine if the AUC for nevirapine correlates with clinical outcome. A distinctive strength of the efavirenz study was that concomitant medications were accounted for in the randomization scheme. Of the level I studies, the nelfinavir trial had the largest sample size, with random assignment of 99 HIV-infected patients to the index (n = 49) and validation (n = 50) groups.
Five anti-infective agents were each studied in 2 separate trials, as described. Classification according to level of evidence is important when there are discrepant results between studies for suggested sampling times to characterize pharmacokinetic parameters. As a general guideline, clinicians may choose to place more weight on results of studies classified as having a higher level of evidence. For example, although the 2 ceftazidime studies suggested 2 different 4-point sampling strategies to characterize AUC, one study had level II-2 evidence and the other had level III evidence. The 2 didanosine studies also yielded discordant limited-sampling strategies. Although this may have been due to differences in the populations studied (adults versus children), one study had level I evidence and the other level II-1 evidence. The 2 studies that described limited-sampling strategies for ciprofloxacin also produced discordant results. The level III study required an additional sample at 2.5 h to best characterize total clearance. However, when restricted to only 2 samples, the selected times were similar to those suggested in the level I study. The 2 nelfinavir studies were difficult to compare, as they characterized 2 different pharmacokinetic parameters (AUC0-12h and AUC0-8h) and provided level I and level III evidence, respectively. The 2 vancomycin studies also developed limited-sampling strategies for prediction of different parameters (clearance and concentration), but again were classified as providing level II-1 and level III evidence, respectively.
In general, the studies identified in this systematic review had small sample sizes, the methods and patient populations were not well described, and a variety of methods were used to determine optimal sampling times. Two studies did not report bias or precision for the variations in sampling times used in development of the limited-sampling strategy; instead, only descriptive statistics of clearance were provided. Methods for determining the sampling times to be used in the limited-sampling strategies included arbitrarily selecting times and use of software to obtain D-optimal times. Use of a computer software program to determine optimal sampling times may yield times that are impractical, as was the case for one ceftazidime study. levitra 10 mg
One study, considered to report level I evidence, randomized data from 83 pharmacokinetic curves into separate index and validation groups, but it is unclear if the 2 groups represented 2 independent sets of patients, as the data were obtained from only 62 patients. The study also did not provide information about the baseline characteristics of the patients, so it was assumed that the “patients” who “ingested their usual morning dose” were receiving zidovudine therapy for HIV and were not volunteers. It would be difficult to apply this limited-sampling strategy in practice, as little is known about the underlying population that was studied. It has been previously shown that a limited-sampling strategy for a drug cannot always be extrapolated to a population other than the one studied. For example, a limited-sampling strategy for didanosine was evaluated in 13 HIV-infected children in a study with level II-1 evidence, but the recommended equations did not reliably predict the AUC in a study of HIV- infected adults. In addition to the expected differences in pharmacokinetics between adults and children, this discrepancy might also have resulted from a difference in the rigour of the evaluations.
Three studies, all considered to present level I evidence, did not report concomitant medications or medical conditions, which limits the generalizability of their findings. In studies of antiretroviral agents, which have numerous potential pharmacokinetic interactions, it would be important to note concomitant antiretrovirals and other medications. In the studies with level I evidence that were identified in this review, patients were prospectively and randomly assigned to index and validation groups, but because the studies were small, it is possible that not all characteristics were balanced between the groups.
A ciprofloxacin study of level I evidence (n = 55) included 20 patients with cystic fibrosis, all less than 25 years of age. Given the pharmacokinetic characteristics specific to patients with cystic fibrosis, such as increased clearance, as well as the pharmacokinetic differences across pediatric and adolescent age groups, it would be desirable to develop and validate a limited- sampling strategy in a study of patients with cystic fibrosis within a narrower age range. The ciprofloxacin study also used 4 different sets of sampling times, ranging from 1 to 13 samples, and selected times on the basis of the dosing regimen used. It would be preferable to characterize a full pharmacokinetic profile for several patients with similar characteristics, all of whom received the same dose, and to attempt validation for all possible combinations of sampling times, to obtain the most precise and least biased limited-sampling strategy. A level I study of a limited-sampling strategy for efavirenz exemplified proper validation procedures, in that patients were randomly assigned to 3 different sets of index and validation groups according to concomitant interacting medications. However, that study also assessed only 3 single sampling times in its evaluation. Although full pharmacokinetic profiles were obtained, the reason for the authors’ choice of 3 time points (8, 12, and 16 h) to estimate the AUC and trough (at 24 h) was
A study of nelfinavir-treated patients, which had level I evidence, provided some baseline comparative information on comorbid conditions between index and validation groups; it also had a more complete evaluation of sampling times than the other level I studies. However, little information on concomitant medication was provided, and, as discussed below, the use of nelfinavir has now fallen out of favour.