Dynamic in Vivo Subtalar Joint Kinematics Measured Using a Skin Marker–Based Protocol

Background The subtalar joint allows complex motion of the foot relative to the leg, the analysis of which has presented a major challenge for researchers. The considerable interpatient variation in structure and function of the subtalar joint highlights the importance of developing a protocol to assess the kinematics in individuals rather than developing an overarching description of function. The use of skin-mounted markers is, therefore, preferable, allowing the noninvasive collection of data. We sought to assess the face validity of a skin-mounted marker–based protocol to measure the in vivo kinematics of the subtalar joint. Methods Thirty participants were recruited using minimal exclusion criteria. A previously tested skin-mounted marker placement protocol was used in conjunction with two CODA MPX 30 sensors to capture data during walking. The data produced were compared with those from previous studies that used bone-mounted markers. Results The results in all three planes represented feasible outcomes compared with those of previous studies, the data falling within the ranges published. Patterns of movement demonstrated are similar to, although not the same as, those shown by previous investigations. Conclusions This study did not produce patterns of movement that exactly matched those of previous investigations. The results were, however, within the ranges previously published, and the patterns of movement shown were feasible. The results suggest the face validity of the method as a means of assessing the in vivo kinematics of the subtalar joint during the stance phase of gait.

Within-Patient Atazanavir Trough Concentration Monitoring in HIV-1-Infected Patients

Objective: Protease inhibitors (PIs) exhibit considerable interpatient pharmacokinetic variability in plasma trough concentrations. Therapeutic drug monitoring (TDM) is occasionally used to guide chronic dosing to achieve target trough concentrations, but its clinical success assumes minimal intrasubject variability. Therefore, our primary objective was to evaluate intrapatient variability in atazanavir (ATV) plasma trough concentrations in HIV-1-infected patients. Design/Methods: In a single-site, prospective, cohort study, patients on atazanavir with or without ritonavir (ATV/r or ATV) for 2 clinic visits were enrolled. Adherence and time since last dose (TSLD) were verified at each visit. ATV was assayed with high-performance liquid chromatography. Intra- and interpatient variation was evaluated using the median intraindividual percentage coefficient of variation (ICV). Results: The mean 24-hour ATV trough concentrations for the first and second visit for the ATV/r group (n = 10) was 598 (CV 84%) and 525 ng/mL (CV 66%), respectively ( P = .511), and 300 (CV 81%) and 434 ng/mL (CV 106%) for the ATV group (n = 4), respectively ( P = .369). Median ICV was 43.1% for all patients (range: 0.6%-107.6%), 38.1% (0.6%-107.6%) for the ATV/r group, and 33.1% (2.3%-87.6%) for the ATV group. Conclusions: Potential intrapatient variability in ATV troughs suggests that repeated measurements may be required to ensure that target values are maintained.

Evaluation of a Deuterium-Labeled Internal Standard for the Measurement of Sirolimus by High-Throughput HPLC Electrospray Ionization Tandem Mass Spectrometry

Background: Matrix effects in HPLC–electrospray ionization–tandem mass spectrometry (HPLC-ESI-MS/MS)1 can cause differences in the ionization of an internal standard (IS) compared with the analyte of interest. Unless sample cleanup or chromatographic conditions eliminate or minimize ion suppression or enhancement, variability in interpatient matrices may cause erroneous results. A stable isotope-labeled IS can be used to minimize analytical interpatient variation. Methods: We used protein precipitation and HPLC-ESI-MS/MS to quantify sirolimus (SIR) with both desmethoxyrapamycin (DMR) and deuterium-labeled sirolimus (SIR-d3) as the IS to analyze a range of whole-blood and extraction-matrix samples, and to estimate recovery, matrix effects, process efficiency, and interpatient variation. We also analyzed a series of blood samples from 72 patients taking SIR, including external proficiency-testing samples, with these ISs. Results: The range of interpatient assay imprecision (CV) values for the SIR assay was consistently lower with SIR-d3 (2.7%–5.7%) than with DMR (7.6%–9.7%). The results obtained with the 2 different ISs for the patient samples showed a linear relationship, but the results were higher with DMR as the IS than with SIR-d3. Conclusions: The use of SIR-d3 as the IS in the high-throughput HPLC-ESI-MS/MS assay of SIR yielded improved results compared with the use of DMR. SIR-d3 appears to be less affected by differences in the ionization of SIR and its IS caused by the variability of interpatient matrices. The IS-related difference in SIR estimation needs further investigation.

Effect of smoking on imatinib pharmacokinetics

2573 Background: Smoking is a potent inducer of the cytochrome P450 1A2 isoenzyme (CYP1A2) and may therefore effect the pharmacokinetics (PK) of drugs metabolized by CYP1A2. Indeed, clinical studies with erlotinib (metabolized by CYP3A4 and also partly by CYP1A2) have shown a major increase in erlotinib clearance in smokers versus non-smokers. The effect of smoking on the PK of imatinib, which is also metabolized by CYP3A4 and partly by CYP1A2, is unknown. We aimed to study the effect of smoking on imatinib PK in order to explain a part of the interpatient variation. Methods: The effect of smoking on the PK parameters was analyzed in 34 patients with gastro-intestinal stromal tumors or soft tissue sarcoma included in the EORTC-STBSG phase I and phase II trials. This cohort included 9 smokers and 25 non-smokers. The daily smoking habits of the study patients were retrieved retrospectively from the patient’s record. PK parameters assessed with NONMEM, version V were clearance (Cl), distribution volume (V), elimination half life (T1/2) and the dose standardized area under the concentration curve (AUC). We considered a 40% reduction in imatinib exposure clinically relevant and this study is adequately powered to detect this difference. Results: The mean PK parameters in the smokers versus the non-smokers group ± SD were: Cl; 9.6 ± 5.5 L/h vs 9.2 ± 4.6 L/h, V; 216.5 ± 114.3 L vs 207.0 ± 116.9 L, T1/2; 16.1 ± 6.0 h vs 16.5 ± 6.0 h, AUC; 133.6 ± 71.0 ng.h/ml.mg vs 142.3 ± 84.0 ng.h/ml.mg. There was no significant difference in PK parameters observed between the smokers and the non- smokers. Conclusion: This retrospective study suggest that the PK of imatinib was not affected by smoking and therefore does not explain the large variation in imatinib PK. No significant financial relationships to disclose.

Association of pharmacokinetic (CYP2C9) and pharmacodynamic (factors II, VII, IX, and X; proteins S and C; and γ-glutamyl carboxylase) gene variants with warfarin sensitivity

We analyzed mutations of 7 vitamin K—dependent protein and cytochrome P450 2C9 genes in 45 patients and investigated whether any contribute to the large interpatient variability in the warfarin dose-effect relationship. Total clearance and daily dose, INR and INR/Cp, were used as pharmacokinetic and pharmacodynamic indexes, respectively. Patients were grouped by genotype based on a single polymorphism and combinations of polymorphisms. Among the 30 sequence variants identified, CYP2C9*3, 165Thr → Met of the factor II gene, -402G → A, (37-bp repeat)n, and -746T → C of the factor VII gene, and (CAA repeat)n of the γ-glutamyl carboxylase gene were selected as candidate polymorphisms. As the analysis of single polymorphisms implied, the highest INR/Cp mean values and the lowest warfarin maintenance doses were observed in patients homozygous for the 165Met, -402G, (37-bp repeat)6 and -746T alleles. Multiple regression analysis revealed that warfarin sensitivity was independently associated with -402G → A, (CAA repeat)n, CYP2C9*3, and 165Thr → Met, which accounted for 50% of variance. These results suggest that part of the considerable interpatient variation is attributable to genetic variation, and the combined genotyping of CYP2C9 and certain vitamin K—dependent protein genes is useful for predicting anticoagulant responses.