Variability In Trough Concentrations Research Articles

LCP-Tacrolimus Extended-Release (Envarsus XR) Use in Adolescent and Young Adult Solid Organ Transplant Recipients.

Limited published experience describes once daily, extended-release tacrolimus (LCP-Tac) use in pediatric solid organ transplantation (SOT), particularly nonrenal SOT. LCP-Tac can simplify immunosuppression (IS) regimens, minimize immediate release-tacrolimus (IR-Tac)-associated adverse effects, and promote adherence. This study describes the successful use of LCP-Tac in adolescent and young adult (AYA) SOT populations. A single-center, retrospective chart review of AYA SOT recipients (age < 25 years) converted from IR-Tac to LCP-Tac. Graft survival, biopsy-proven acute rejection (BPAR), infection rates, estimated glomerular filtration rate (eGFR), and pill burden were assessed at five time points postconversion (1, 3, 6, 12, and 24 months). Intrapatient variability of tacrolimus, as assessed by coefficient of variability (CV%), was also analyzed. Twenty-nine AYA SOT recipients (19 heart, 6 kidney, and 4 liver) were converted to LCP-Tac, with a median age of 17.4 years at conversion. Conversion, mainly due to perceived or identified medication nonadherence, occurred at a median of 5.4 years posttransplant. No graft loss occurred within 24 months of conversion, and BPAR incidence rate was consistent with previous reports for these populations. Only one patient experienced CMV infection. Renal function remained stable postconversion. Successful conversion from IR-Tac to LCP-Tac was demonstrated in AYA heart, kidney, and liver transplant recipients. These AYA SOT recipients experienced reduced pill burden and improved tacrolimus trough concentration variability. However, the impact on medication adherence warrants further investigation. Future research should explore the targeted use of LCP-Tac to enhance IS tolerability and medication adherence in young SOT populations.

Apixaban plasma concentrations in patients with obesity

PurposeRoutine therapeutic drug monitoring of apixaban is currently not recommended but may however be warranted in some situations and for some patient groups to provide better and safer treatment. Due to limited data on apixaban concentrations in different subpopulations, it is still unclear which group of patients could possibly gain from monitoring. The purpose of this study was to examine apixaban exposure in patients with obesity compared with normal-weight patients.MethodsForty patients with obesity (mean BMI 39.4 kg/m2) and 40 controls with normal weight (mean BMI 23.4 kg/m2), treated with apixaban 5 mg twice daily were included. The patients were matched for age, sex, and renal function. Trough and peak apixaban concentrations were measured with LC‒MS/MS methodology.ResultsThe median trough concentrations in patients with obesity (58.7, range 10.7–200.7 ng/ml) were slightly higher than those in patients with normal weight (52.0, range 31.0–150.9 ng/ml) (p < 0.05). Notably, the variability in trough concentration was considerably higher in patients with obesity. Peak concentrations were similar in both groups, with a median of 124.5 ng/ml (range 82.0–277.5) and 113.5 ng/ml (range 75.5–334.6) in patients with obesity and normal weight, respectively.ConclusionApixaban exposure did not vary substantially between obese and normal weight matched controls, implying that general dose adjustments are not required. However, vast interindividual variability was observed in patients with obesity, suggesting that measuring the concentrations could be valuable for specific patients. Further research is needed to identify which specific patients may benefit from this approach.

Quantification of belatacept by liquid chromatography-tandem mass spectrometry in human plasma: Application to a pharmacokinetic study in renal transplant recipients

Therapeutic drug monitoring is the cornerstone of immunosuppressive treatment in transplantation. The immunosuppressive drugs used in kidney transplant patients are mostly comprised of biologics, including therapeutic monoclonal antibodies (mAbs) and fusion proteins. Therefore, a specific and sensitive analytical technique that can universally quantify mAbs, as well as fusion proteins, is essential for clinical pharmacokinetics studies.In this short communication, we describe the validation of a liquid chromatography tandem mass-spectrometry (LC-MS/MS) method for quantification of the fusion protein belatacept in the plasma of kidney-transplant patients. Sample preparation was based on our previously published and implementable electrospray ionization LC-MS/MS method that allows the simultaneous quantification of seven mAbs. Immunocapture was made possible by the Fc domain of belatacept and identification/quantification by the choice of MRM transitions of peptides. The temporal evolution of the belatacept concentration after intravenous infusion and inter-individual variability of trough concentrations were assessed in 17 human plasma samples.The belatacept calibration curves were linear from 1 to 200 mg.L−1 and within-day and between-day accuracy and precision fulfilled Food and Drug Administration validation criteria. Residual belatacept concentrations (n = 8) ranged from 5.1 to 15.0 mg.L−1, with a median of 8.9 mg.L−1 and an inter-individual CV of 33.0%.Our generic LC-MS/MS method allows the quantification of fusion proteins, such as belatacept, and could be used for therapeutic drug monitoring. This method provides a useful tool to study the intra-patient variability of belatacept and the association between belatacept exposure and its therapeutic effects.

Impact of once-daily ER-Tac on trough concentration variability in a stable AYA renal transplant recipient cohort.

Successful renal transplantation requires complex medication regimens that rely on strict adherence to be effective. Variability in immunosuppression exposure, specifically tacrolimus, is associated with poor allograft outcomes. Wide intra-patient variability of tacrolimus trough concentrations (Vtac) is likely, in part, attributable to regimen complexity and poor medication adherence. Once-daily tacrolimus formulations create opportunity to simplify therapeutic regimens, and this study aims to evaluate their impact on Vtac and ultimately transplant outcomes. This retrospective cohort study investigated stable (AYA) renal transplant recipients converted from (IR-Tac) to (ER-Tac). Subjects served as their own controls. Vtac was assessed by measuring the (SD) of serial tacrolimus trough concentrations prior to and at four time points post-conversion to ER-Tac over 24-month follow-up. Secondary outcome measures included graft function, infection rates, and effect on modifiable treatment-related factors. Twenty-eight AYA subjects were converted from IR-Tac to ER-Tac. Vtac significantly improved following conversion and was sustained for 24months (Vtac0 2.32 vs. Vtac24 1.11, p .017). Renal function remained stable, and (BPAR) rates were modest (14%). Mean pill burden was reduced by 15%, and 42.9% of subjects achieved a once-daily medication regimen. Conversion from IR-Tac to ER-Tac in this AYA population significantly improved Vtac with sustained effect over 2years. This effect is likely attributable in part to simplification of the medication regimen and presumably improved medication adherence. Such conversion does not appear to compromise graft function for at least 2years post-conversion.

The influence of CYP2C19 polymorphisms on voriconazole trough concentrations: Systematic review and meta-analysis.

Voriconazole primary metabolism is catalysed by CYP2C19. A large variability of trough concentrations in patients with invasive fungal infection treated with voriconazole has been observed in clinical practice. It remains controversial whether the CYP2C19 polymorphisms are responsible for voriconazole metabolism in the individual variation. The primary aim of this study was to assess the effect of CYP2C19 polymorphisms on voriconazole trough concentrations. Following a systematic literature review, we performed a meta-analysis for mean differences (MD) of voriconazole trough concentrations (Cmin ), voriconazole dosage adjusted trough concentrations (Cmin /D) and for risk ratio (RR) of the proportion of patients in the target therapeutic range between pairwise comparisons of CYP2C19 phenotypes. Compared with normal metabolisers (NMs), intermediate metabolisers (IMs) (MD: 0.82, 95% CI: 0.57 to 1.07, I2 =44%, p<.00001) or poor metabolisers (PMs) (MD: 1.59, 95% CI: 1.14 to 2.05, I2 =46%, p<.00001) had significantly higher voriconazole Cmin (μg·ml-1 ), while rapid metabolisers (RMs) had significantly lower voriconazole Cmin (MD: -0,87, 95% CI: -1.35 to -0.38, I2 =0%, p=.0004). In addition, IMs had significantly lower Cmin than PMs (MD: -0.59, 95% CI: -0.97 to -0.20, I2 =22%, p=.003). Similarly, the Cmin /D (μg·kg·ml-1 ·mg-1 ) was significantly higher in IMs (MD: 0.13, 95% CI: 0.05 to 0.22, I2 =0%, p=.002) and PMs (MD: 0.20, 95% CI: 0.07 to 0.34, I2 =0%, p=.003) than that in NMs, and also, IMs had significantly lower Cmin /D than PMs (MD: -0.11, 95% CI: -0.14 to -0.08, I2 =0%, p<.00001). Furthermore, PMs had a significantly higher proportion of the target therapeutic range than NMs (RR: 1.34, 95% CI: 1.09 to 1.64, I2 =50%, p=.005). Compared to NMs, IMs and PMs had higher voriconazole trough concentrations, especially in Asians, while RMs had lower voriconazole trough concentrations. In addition, PMs had a higher proportion of the target therapeutic range than NMs, especially in Asians. CYP2C19 genotyping is expected to be used to preemptively guide the individualisation of voriconazole in clinical practice.

Exploratory Analysis of the Impact of an mHealth Medication Adherence Intervention on Tacrolimus Trough Concentration Variability: Post Hoc Results of a Randomized Controlled Trial.

Medication nonadherence is a leading cause of late allograft loss in kidney transplantation (KT). Tacrolimus trough coefficient of variation (CV), measured using the coefficient of variation, is strongly correlated with acute rejection, graft function, and graft loss. The objective of this study was to determine if this mobile health (mHealth) intervention aimed at improving medication adherence in a nonadherent KT population would affect high intrapatient tacrolimus variability. A 6-month, prospective, parallel-arm, randomized controlled clinical trial was conducted to determine the effects of an mHealth intervention on tacrolimus CV. Intervention arm participants utilized an electronic medication tray and an mHealth app to monitor home-based adherence. Tailored motivational reinforcement messages were delivered to promote competence for adherence. Tacrolimus CV was measured using a 12-month rolling average, assessed at monthly intervals (6-month intervention period and 6 months after completion of the study); 80 were included, 40 in each arm. At baseline, tacrolimus CV was similar between arms (37% ± 15% intervention, 37% ± 13% control, P = 0.894). Patients randomized to the intervention had a significant reduction in mean 12-month tacrolimus CVs (P = 0.046) and a significant improvement in the proportion achieving low tacrolimus CV (tacrolimus CV < 40%; P = 0.001), as compared with the control arm. High tacrolimus CV is a risk factor for acute rejection and graft loss; these results offer the potential promise of improved medication adherence and clinical outcomes through the use of innovative technology.

The Association of Tacrolimus Formulation Switching with Trough Concentration Variability: A Retrospective Cohort Study of Tacrolimus Use Post-Kidney Transplantation Based on National Drug Code (NDC) Numbers.

IntroductionIt was hypothesized that patients experiencing at least one tacrolimus formulation switch may require more frequent therapeutic drug monitoring, subsequent dose adjustments, and a potential for untoward clinical outcomes than patients who remain on a single formulation.MethodsEligible patients were adult kidney transplant recipients with stable renal function at month 3 post-transplant and no evidence of acute rejection, receiving an oral, tacrolimus-based regimen. Patients were categorized into two groups (fixed or variable formulation) using the US National Drug Code (NDC) on the basis of tacrolimus formulation usage over the 12-month period.ResultsA total of 305 patients were enrolled from four US transplant centers; 44 (14.4%) received multiple formulations and 261 (85.6%) received a single formulation. Mean number of tacrolimus dose adjustments and mean cumulative milligram dose change were not statistically different between the two groups. Mean trough-to-dose ratio, frequency of trough level measurements, and mean number of excursions above 120% or below 80% of the patient’s mean trough concentration were significantly higher in the variable compared to the fixed formulation group.ConclusionA variable tacrolimus formulation regimen was associated with a higher frequency of trough level measurements and a greater number of excursions in trough levels compared with continuing on a fixed formulation regimen of tacrolimus in this retrospective chart review study.FundingAstellas Pharma Global Development, Inc.Plain Language SummaryPlain language summary available for this article.

Long-lasting immunosuppressive effects of tacrolimus-loaded micelle NK61060 in preclinical arthritis and colitis models.

Tacrolimus (TAC) is an important drug for inflammatory diseases. However, TAC has several limitations, such as variable trough concentrations among individuals and a high medication frequency. In this study, we created NK61060, a novel micellar TAC formulation, to circumvent these disadvantages. Immunosuppressive activity of NK61060 was determined in the collagen-induced arthritis rat model, mannan-induced arthritis mouse model and dextran sodium sulfate-induced colitis mouse model. The pharmacokinetics and toxicology of NK61060 were evaluated in those models. In arthritis and colitis models, NK61060 exhibited superior immunosuppressive activity compared with that of TAC. Pharmacokinetic and toxicological analyses indicated that NK61060 had a wider safety margin and could be administered at a reduced medication frequency. NK61060 mitigates the trough concentration variability and the medication frequency and it may be a safer and more effective option for use in clinical settings. Further studies are needed to determine its clinical usefulness.

A microscale HPLC-UV method for the determination of latamoxef in plasma: An adapted method for therapeutic drug monitoring in neonates.

Latamoxef, a broad-spectrum anti-bacterial agent of the β-lactam antibiotics, is used off-label in treatment of neonatal sepsis. Large inter-individual variability and uncertainty of treatment make therapeutic drug monitoring (TDM) useful to optimize antimicrobial therapy. The objective of this study was to develop and validate a simple, selective and reliable HPLC method for the determination of latamoxef in small volumes of plasma, which could be used in neonatal TDM. After a simple protein precipitation, analytes were separated with liquid chromatography and quantified by UV detection, with tinidazole as the internal standard. The calibration range was linear from 3.0 to 60.0 μg/mL. Intra- and inter-day precisions were < 7.2%. The acceptance criteria of accuracy (between 85 and 115%, 120% for lower limit of quantification) were met in all cases. A plasma volume of 50 μL was required to achieve the limit of quantification of 3.0 μg/mL. The TDM results showed a large variability in trough concentrations. A large number of patients were underdosed, highlighting the unmet need for TDM to optimize latamoxef therapy in neonates.

Tacrolimus Trough Concentration Variability and Disparities in African American Kidney Transplantation.

Low tacrolimus concentrations have been associated with higher risk of acute rejection, particularly within African American (AA) kidney transplant recipients; little is known about intrapatient tacrolimus variabilities impact on racial disparities. Ten year, single-center, longitudinal cohort study of kidney recipients. Intrapatient tacrolimus variability was assessed using the coefficient of variation (CV) measured between 1 month posttransplant and the clinical event, with a comparable period assessed in those without events. Pediatrics, nontacrolimus/mycophenolate regimens, and nonrenal transplants were excluded. Multivariable Cox regression models were used to analyze data. One thousand four hundred eleven recipients were included (54.4% AA) with 39 521 concentrations used to assess intrapatient tacrolimus CV. Overall, intrapatient tacrolimus CV was higher in AAs versus non-AAs (39.9 ± 19.8 % vs 34.8 ± 15.8% P < 0.001). Tacrolimus variability was a significant risk factor for deleterious clinical outcomes. A 10% increase in tacrolimus CV augmented the risk of acute rejection by 20% (adjusted hazard ratio, 1.20, 1.13-1.28; P < 0.001) and the risk of graft loss by 30% (adjusted hazard ratio, 1.30, 1.23-1.37; P < 0.001), with significant effect modification by race for acute rejection, but not graft loss. High tacrolimus variability (CV >40%) was a significant explanatory variable for disparities in AAs; the crude relative risk of acute rejection in AAs was reduced by 46% when including tacrolimus variability in modeling and reduced by 40% for graft loss. These data demonstrate that intrapatient tacrolimus variability is strongly associated with acute rejection in AAs and graft loss in all patients. Tacrolimus variability is a significant explanatory variable for disparities in AA recipients.

O-4 Analysis of voriconazole monitoring data in children with onco-haematological diseases

<h3>Background</h3> Voriconazole (VCZ) is a triazole antifungal agent widely used in immunocompromised patients with suspected or proved invasive fungal infection. The achievement of therapeutic range (1–5 mg/L) is clinically important to maximise VCZ efficacy. Many factors are known to influence its pharmacokinetics characterised by a wide inter and intra-individual variability in trough concentrations (age, genotype, comedications.). VCZ is metabolised primarily by CYP2C19 producing the main metabolite, N-oxide VCZ, pharmacologically inactive but potentially responsible for the occurrence of toxicities. Polymorphisms on 2 C19 gene induce different phenotypes impacting the VCZ plasma levels. Our objectives are to evaluate the variability of voriconazole trough concentrations and identify practical issues to optimise and interpret such monitoring data in children and adolescents with oncohaematological disease. <h3>Methods</h3> Children (&lt;18 years old) with oncohaematological disease treated with VCZ for documented or suspected invasive fungal infection who had samples drawn for VCZ monitoring from January 2014 to December 2016 were included in the study. Demographic data (age, sex, weight, initial disease and biological parameters) were collected for each patient from medical prescription or informatic extraction. Indication of VCZ, detailed treatment and monitoring data were also collected. The statistical analyses were performed using SPSS v24.0. For some analysis, patients were divided in two group based on prescription recommendations: Group 1 (G1) included children&lt;2 years, 2–12 years and 12–14 years&lt;50 kg and Group 2 (G2) included adolescents&gt;12–14 years&gt;50 kg (instead of 40 kg) and adolescents&gt;14 years&gt;40 kg. <h3>Results</h3> A total of 380 trough concentrations at steady state (C0,ss) were identified in 79 patients (46 girls and 33 boys), 126 concentrations had to be excluded (66 were not at steady state, 22 were not trough levels, 38 had incomplete medical or biological information). Median age at the initiation of VCZ was 9 (1–16.5) years. The majority of patients had acute leukaemia (60.8%) and received VCZ after allogenic hematopoietic stem cell transplantation. Median oral doses in G1 was 8.1 (2.5–13.8) mg/kg (n=38) vs 3.9 (2.4–6.0) mg/kg (n=13) in G2. Median intravenous doses in G1 was 7.8 (4.2–13.3) mg/kg (n=22) vs 3.7 (2.8–4.6) mg/kg (n=6) in G2. In the global cohort, 45.6% attain therapeutic range at first monitoring, 46.8% had C0,ss below 1 mg/L and 7.6% had C0,ss over 5 mg/L. Forty-one patients were treated with recommended doses but only 53% of them reach therapeutic range. There was no impact of age, sex, biological parameters, indication of VCZ on C0,ss values. The number of C0,ss in the therapeutic range increases with the number of monitoring per pa-tient following dosage adaptation. <h3>Conclusion</h3> There is a wide variability in VCZ trough con-centrations and our data shows that conditions should be precisely defined. for optimal monitoring. It is necessary to identify factors which contribute to this variability to individualise treatment for each patient and to take them into consideration for establishing a standardised thera-peutic drug monitoring.

Teicoplanin use in adult patients with haematological malignancy: Exploring relationships between dose, trough concentrations, efficacy and nephrotoxicity

In 2010, our hospital introduced a higher target teicoplanin trough concentration of ≥20mg/L by Day 3 for haematological malignancy patients. This study aimed to explore whether target trough concentrations were achieved, to identify factors associated with trough concentrations attained, and to assess clinical efficacy with teicoplanin treatments and nephrotoxicity. This was a retrospective, single-centre, cohort study of 172 teicoplanin treatments in 104 adults with haematological malignancy. Mixed-effects regression was used to evaluate factors affecting trough concentrations, and logistic regression was used to assess the relationship between trough concentrations and treatment outcomes. Nephrotoxicity was assessed using the RIFLE criteria. Considerable variability in trough concentrations was observed, with trough concentrations ≥20mg/L rarely achieved early in therapy. A mixed-effects regression model explaining 52% of the variation in trough concentrations was developed. Dose and day of therapy were positively associated with trough concentration, whilst estimated renal function and, interestingly, acute myeloid leukaemia diagnosis were negatively associated (P<0.05). Results suggested a positive relationship between trough concentration and the likelihood of a favourable outcome for coagulase-negative staphylococcal central line-associated bloodstream infections. Elucidation of a specific target concentration requires further investigation. Teicoplanin was well tolerated renally. Findings suggest a risk of underexposure if conventional teicoplanin doses are used in haematological malignancy patients. Given the variability in trough concentrations observed, the identified factors affecting trough concentrations attained and the suggested link with clinical outcome, individualised initial dosing followed by therapeutic drug monitoring is recommended to ensure early adequate exposure in this vulnerable patient group.

A UK analysis of the cost of switching renal transplant patients from an immediate-release to a prolonged-release formulation of tacrolimus based on differences in trough concentration variability

Background and aims:Randomized controlled trials have shown that a once-daily prolonged-release (PR) tacrolimus formulation (PR tacrolimus; Advagraf), is non-inferior to a twice-daily immediate-release (IR) tacrolimus formulation (IR tacrolimus; Prograf) in terms of biopsy-proven acute rejection, graft failure and mortality in renal transplant recipients. However, relative to IR tacrolimus, PR tacrolimus exhibits reduced tacrolimus trough concentration variability, which has been associated with reduced graft failure. Based on these data, the present study evaluated the cost of switching UK renal transplant patients from IR tacrolimus to PR tacrolimus.Methods:UK-specific data on acute rejection, graft failure, and mortality were used to construct a budget impact model to assess the costs of switching from IR tacrolimus to PR tacrolimus on a 1:1 mg:mg basis. The model assumed that 3.1% of patients on PR tacrolimus had high tacrolimus trough concentration variability compared with 17.4% on IR tacrolimus, based on a study comparing PR tacrolimus and IR tacrolimus pharmacokinetics. A relative graft failure risk of 2.38 was applied to high variability patients based on data from a tacrolimus variability study in which 10/148 patients with low variability experienced graft failure, compared with 24/149 in the high variability group. Cost data were taken from the British National Formulary and 2012–2013 NHS tariff information.Results:The mean per-patient cost (including tacrolimus, concomitant immunosuppressive medications, dialysis after graft failure, and treatment for acute rejection) was GBP 26,941 (standard deviation [SD] = GBP 2765) with PR tacrolimus vs GBP 30,356 (SD = GBP 3085) for IR tacrolimus over a 5-year period, corresponding to a saving of GBP 3415 (SD = GBP 516) per patient or GBP 341,500 in a hypothetical 100-patient transplant center. Cost savings were driven primarily by lower dialysis costs resulting from the lower proportion of PR tacrolimus patients with high tacrolimus trough concentration variability (leading to lower graft failure risk).Limitations:The main limitation of the study was the use of heterogeneous data sources to capture the effect of within-patient variability on graft failure. The most important difference between the studies was the definition of the threshold between low and high within-patient variability. This was explored in sensitivity analyses in which the inter-arm difference in the inter-arm proportions of patients with high and low variability was abolished.Conclusions:Converting UK renal transplant recipients from IR tacrolimus to PR tacrolimus was associated with lower pharmacy and dialysis costs.

PUK8 - An Analysis of the Cost of Switching Renal Transplant Patients from an Immediate-Release to a Prolonged-Release Formulation of Tacrolimus Based on Differences in Trough Concentration Variability in the United Kingdom

PUK8 - An Analysis of the Cost of Switching Renal Transplant Patients from an Immediate-Release to a Prolonged-Release Formulation of Tacrolimus Based on Differences in Trough Concentration Variability in the United Kingdom

Therapeutic drug monitoring for imatinib: Current status and Indian experience

Imatinib is the current gold standard for treatment of chronic myeloid leukemia (CML). Recent pharmacokinetic studies have shown considerable variability in trough concentrations of imatinib due to variations in its metabolism, poor compliance, or drug-drug interactions and highlighted its impact on clinical response. A trough level close to 1000 ng/mL, appears to be correlated with better cytogenetic and molecular responses. Therapeutic Drug Monitoring (TDM) for imatinib may provide useful added information on efficacy, safety and compliance than clinical assessment alone and help in clinical decision making. It may be particularly helpful in patients with suboptimal response to treatment or treatment failure, severe or rare adverse events, possible drug interactions, or suspected nonadherence. Further prospective studies are needed to confirm relationship between imatinib plasma concentrations with response, and to define effective plasma concentrations in different patient populations.

Variability of antibiotic concentrations in critically ill patients receiving continuous renal replacement therapy

In critically ill patients receiving continuous renal replacement therapy, we aimed to assess the variability of antibiotic trough concentrations, the influence of effluent flow rates on such concentrations, and the incidence of suboptimal antibiotic dosage. Prospective, observational, multicenter, pharmacokinetic study. Four tertiary intensive care units within the multicenter RENAL randomized controlled trial of continuous renal replacement therapy intensity. Twenty-four critically ill adult patients with acute kidney injury receiving ciprofloxacin, meropenem, piperacillin/tazobactam, or vancomycin during continuous renal replacement therapy. We obtained trough blood samples and measured antibiotic concentrations. We obtained data from 40 dosing intervals and observed wide variability in trough concentrations (6.7-fold for meropenem, 3.8-fold for piperacillin, 10.5-fold for tazobactam, 1.9-fold for vancomycin, and 3.9-fold for ciprofloxacin). The median (interquartile range) trough concentrations (mg/L) for meropenem was 12.1 (7.8-18.4), 105.0 (74.4-204.0)/3.8 (3.4-21.8) for piperacillin/tazobactam, 12.0 (9.8-16.0) for vancomycin, and 3.7 (3.0-5.6) for ciprofloxacin. Overall, 15% of dosing intervals did not meet predetermined minimum therapeutic target concentrations, 40% did not achieve the higher target concentration, and, during 10% of dosing intervals, antibiotic concentrations were excessive. No difference, however, was found between patients on the basis of the intensity of continuous renal replacement therapy; this effect may have been obscured by differences in dosing regimens, time off the filter, or altered pharmacokinetics. There is significant variability in antibiotic trough concentrations in critically ill patients receiving continuous renal replacement therapy, which did not only appear to be influenced by effluent flow rate. Here, empirical dosing of antibiotics failed to achieve the target trough antibiotic concentration during 25% of the dosing intervals.

Intermittent administration of ceftazidime to burns patients: influence of glomerular filtration

The pharmacokinetics of ceftazidime, the antibiotic of choice for treating acute P. aeruginosa infections, may be modified in burns patients. The aim of this study was to identify the factors causing variations in the serum antibiotic concentrations in bums patients. 30 patients with serious burns were randomly divided into two groups. Group 1 received a dose of ceftazidime of 2 x 3 g/24 hours. The second group received the same dose but divided into 6 administrations. Blood samples were taken at 24 (M1) and 48 hours (M2) after the start of treatment and the peak and trough serum concentrations of ceftazidime measured by HPLC. Depending on the results, frequency and/or dose was modified to obtain trough concentrations (Cmin) equal to 16 mg/l, i.e. 4 times the MIC. Either the same dose was maintained, but mostly divided up, or it was increased to 1 g x 8 administrations or it was decreased to 1 g x 4 or 1 g x 3. The serum concentrations of ceftazidime obtained were analyzed taking into account the characteristics of the burns patients (multivariate correlation). From the first sample (M1) Cmin was lower than the target concentration in 50% of the patients in Group 1 and 20% in Group 2. The modification of the dosing regimen put into place after the first analysis, led to the patients being further divided into four groups before the second blood sampling. Finally, 5 patients ended up in Group 1. In all patients and for all administration times, a negative correlation was found between Cmin and the creatinine clearance, calculated by using Cockcroft's formula. This study highlights the peculiarities of ceftazidime pharmacokinetics seen in burns patients with high interindividual variability. Based on Cmin monitoring and a predefined therapeutic range, dose adjustment was often required. Ceftazidime clearance is correlated with creatinine clearance (Cockcroft's formula), suggesting that this parameter could be used for a priori or a posteriori dose individualization. To respect the summary of the product characteristics (SPC) and reduce the variability in trough concentrations, the dose should be fractionated (1 g x 6) over a 24-hour period or even given as a continuous infusion. Trough concentrations must be evaluated to adapt the dosage regimen to attain target concentrations of 4 x the MIC.

Variability in non‐nucleoside reverse transcriptase and protease inhibitors concentrations among HIV‐infected adults in routine clinical practice

The objective of this study was to assess interindividual variability in plasma trough concentrations of non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI) among HIV-infected adults in an outpatient routine clinical practice setting. The study included 117 patients who attended our clinic for routine outpatient blood tests and who were receiving antiretroviral therapy which included NNRTI or PI. Patients were not informed that drug concentrations were going to be assessed until blood sampling. The time of the last antiretroviral treatment intake and blood sampling were recorded. Drug concentrations were considered optimal if they were above the proposed minimum effective concentration. In addition, efavirenz, nevirapine and atazanavir concentrations were considered potentially toxic if they were higher than 4.0 mg l(-1), 6.0 mg l(-1), and 0.85 mg l(-1), respectively. Overall, interindividual variability in NNRTI and PI plasma concentrations was approximately 50%, and only 68.4% of the patients had drug concentrations within the proposed therapeutic range. Inappropriate adherence only explained 35% of subtherapeutic drug concentrations. Interindividual variability in trough concentrations of NNRTI and PI among HIV-infected adults is large in routine clinical practice, with drug concentrations being outside the therapeutic window in a significant proportion of patients. Therapeutic drug monitoring may be useful to guide antiretroviral therapy in clinical practice.

Determination of Imatinib Plasma Levels by High Performance Liquid Chromatography (HPLC): Evaluation of Pharmacokinetic Variability and Haematological Consequences.

Imatinib exerts a potent and selective inhibition of tyrosine kinase Bcr-Abl. It is currently used for treatment of chronic myeloid leukaemia (CML) and acute leukaemia (AL). Pharmacokinetic data indicate large variability especially in plasma exposure with many factors which could be involved (absorption, metabolism, drug-drug interactions). Compliance must also be taken in count. The aim of this study was to determine the variability of imatinib plasma concentrations in a « natural clinical setting» (outpatients on long-term treatment for CML or AL). Secondary objective was to perform a pilot assessment of the relationship between imatinib plasma concentration and clinical outcomes.Analysis was performed by HPLC. Sample treatment (500 μL of patient plasma) consisted of a liquid-solid extraction. Imatinib and internal standard (CGP 53716) were eluted on a Lichrosorb® RP8 column with methanol-THF-sodium acetate buffer 0.1M pH 5. Detection was performed with UV spectrophotometer (262 nm). The limit of quantification was set at 200 ng/mL. Within-day and inter-day precisions were lower than 15%.Blood samples were collected at steady-state (trough and peak values, ie before and 3h after drug administration) in outpatients treated for CML or AL with one imatinib daily dose, at clinical visits. Clinical evolution was considered as successful when following responses were obtained: complete haematological response within 3 months, or major cytogenetic response within 6 months, or complete cytogenetic response within 12 months, or major molecular response within 18 months in the CML group, and complete cytogenetic response after induction in the AL group.68 imatinib measurements were obtained from 24 patients (13 CML and 11 AL). Mean age was 49 years (range 21–74) and weight was 73 kg (49–100). In patients receiving imatinib 400mg daily dose, trough and peak concentrations were respectively 1.60 ±1.28 (0.5–5.1) μg/mL (n=19), and 3.51 ±3.04 (1.0–11.1) μg/mL (n=9). In patients treated with a daily dose 600mg, trough and peak concentrations were respectively 2.62 ±2.10 (0.8–6.5) μg/mL (n=22), and 5.85 ±4.15 (1.2–15.1) μg/mL (n=18).Variability of trough concentrations of imatinib were 80% in both groups (400 and 600mg). 18 patients were evaluable. 15 efficient responses were obtained and all these patients showed imatinib trough levels above 0.5 μg/mL (target plasma concentration required to induce death of leukaemic cells). 3 patients with failure showed nevertheless imatinib trough levels of 1.5, 1.8 and 4.5 μg/mL. 3 patients showed accumulation of imatinib (trough levels higher than 5.0 μg/mL) due to hepatic impairment but without side effects.The method of analysis is very simple, sensitive and specific. Our results confirm the large variability of imatinib plasma concentrations and are consistent with previous results. These preliminary results showed a « safe » imatinib exposure which leads to therapeutic concentrations (higher than 0.5 μg/mL). Therapeutic drug monitoring seems to be not systematicaly necessary but could be reserved to specific cases of poor compliance, major risks of interaction or cases of failure or resistance. Studies of correlation with a larger cohort of patients is necessary to clarify the role of imatinib therapeutic drug monitoring for improving its use.

Variability in non‐nucleoside reverse transcriptase and protease inhibitor concentrations among HIV‐infected adults in routine clinical practice

The objective of this study was to assess interindividual variability in trough concentrations of plasma of non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI) among HIV-infected adults in a routine outpatient setting. One hundred and seventeen patients who attended our clinic for routine blood tests, and who were receiving antiretroviral therapy which included NNRTI or PI were studied. Patients were not informed that drug concentrations were going to be measured until blood sampling. The times of the last antiretroviral dose and of blood sampling were recorded. Drug concentrations were considered optimal if they were above the proposed minimum effective value. In addition, efavirenz, nevirapine and atazanavir concentrations were considered potentially toxic if they were > 4.0 mg l(-1), > 6.0 mg l(-1) and > 0.85 mg l(-1), respectively. Overall, interindividual variability of NNRTI and PI concentrations in plasma was approximately 50%, and only 68.4% of the patients had drug concentrations within the proposed therapeutic range. Poor adherence explained only 35% of subtherapeutic drug concentrations. Interindividual variability in trough concentrations of NNRTI and PI among HIV-infected adults is large in routine clinical practice, with drug concentrations being outside the therapeutic window in a significant proportion of patients. These findings provide further evidence that therapeutic drug monitoring may be useful to guide antiretroviral therapy in clinical practice.