Comparison of Mw\Pharm 3.30 and Mw\Pharm ++ (Windows version) software for PK/PD monitoring of vancomycin: A priori modeling.

OBJECTIVE: To evaluate the possibility of population-based dose optimization with the aid of MwPharm modeling and to find the best model in the Windows version (WIN). MATERIALS: 25 patients repeatedly examined for vancomycin (mean age 63 ± 14 years, body weight 88 ± 21 kg, median dose 1 g/12 h). METHODS: Trough concentrations predicted by WIN models "vancomycin_adult_k_C2", "#vancomycin_adult_C2", "vancomycin_adult_C2", and "vancomycin adult" DOS model (DOS) were compared with the measured value. STATISTICS: The percentage prediction error (%PE) calculated as (predicted - measured)/measured values, Blandt-Altman plot, root mean square error (RMSE), Pearson's coefficient of rank correlation (R). Data is presented as mean ± SD. Student's t-test was used for prediction precision evaluation. RESULTS: The %PE varied from +44.4 ± 65.2% to +76.5 ± 84.3%, p < 0.001. "#vancomycin_adult_C2" model produced the lowest %PE among WIN models as well as the lowest RMSE (79) and Blandt-Altman bias (-4.01 ± 7.59), but the Pearson's correlation (0.6843, p = 0.0002) was less tight. DOS model produced the second lowest RMSE (81), %PE (+45.9 ± 66.6%), and Blandt-Altman bias (-4.83 ± 6.97) and highest Pearson's R (0.7847, p < 0.0001). "vancomycin_adult_C2" produced the third best prediction: RMSE (113), %PE (62.8 ± 92.6%), Blandt-Altman bias (-6.78 ± 11.2) but Pearson's R was the poorest (0.5773, p = 0.0025). CONCLUSION: The lowest %PE and highest Pearson's R were achieved by the "#vancomycin_adult_C2" model. Due to the poor predictive performance of all MwPharm versions and models, we find all of them unsuitable for a priori vancomycin dosing management. Other software should be evaluated for routine use.

Was it necessary to change the therapeutic range of topiramate?

AIMS: The Norwegian Association for Clinical Pharmacology in their National Guidelines decreased the therapeutic range (TR) of topiramate (TPM) from 5-20 mg/L to 2-10 mg/L. The objective of this study is to ascertain which TR produces better clinical outcomes. METHODS: The data sources were request forms for routine therapeutic drug monitoring (TDM) of TPM. Concentration dependent adverse drug reactions (ADRs) were evaluated in 1721 samples taken pre-dose. Seizure frequency analysis was performed in 294 samples of monotherapy. Statistical analysis was performed using Prism 5.0, GraphPad Instatt: One-way ANOVA with Bonferroni correction for median plasma level (PL) and χ2 -test with Bonferroni correction for seizure frequency and for distribution of PL according to TR 5-20 mg/L and intervals <2, 2-5, 5-10, 10-20, >20 mg/L. RESULTS: Better seizure control was found in children both in the whole cohort (without seizure 49% vs 37% adults), as well as in monotherapy (56% vs 44%), in children with PL 5-20 mg/L vs <5 mg/L (65% vs 44%) and in children with PL 5-10 mg/L vs <2 mg/L (63 vs 14%). PL in seizure-free patients did not differ from those with seizure. Seizure control was poorer in the period 2003-2005 compared to 2006-2011. ADRs reported in 38 samples (2.8%) were not related to PL. CONCLUSIONS: Change of TR is not recommended.

Comparison of Mw\Pharm 3.30 and Mw\Pharm ++, a Windows version of pharmacokinetic software for PK/PD monitoring of vancomycin. Part 1: A-posteriori modelling.

BACKGROUND AND OBJECTIVES: For a long time, the Mw\Pharm software suite (MEDI\WARE, Prague, Czech Republic/ Groningen, Netherlands) has been used for PK/PD modelling in therapeutic drug monitoring (TDM). The aim of this study was to find the best model in the newer Windows Mw\Pharm++ 1.3.5.558 version (WIN). METHODS: 25 patients were repeatedly examined for vancomycin (mean age 63±14 years, body weight 88±21 kg, median dose 1 g/12 h). Trough concentrations predicted a-posteriori by WIN models "vancomycin_adult_k_C2", "#vancomycin_adult_C2", "vancomycin_adult_C2" were compared with the measured value and "vancomycin adult" DOS 3.30 model (DOS). STATISTICS: Percentage prediction error (%PE) calculated as (predicted-measured)/measured values, or WIN-DOS/DOS - data presented as mean±SD, RMSE, Blandt-Altman plot - data presented as bias±SD (95% limits of agreement), Pearson's coefficient of rank correlation (R), Student's t-test. Statistical analysis was performed using GraphPad Prism version 5.00 for Windows. RESULTS: The mean%PE in vancomycin predicted values varied from -4.5% ± 33.6 to -8.2% ± 39.3. The%PE between WIN and DOS models varied from -0.2% ± 24.5% to 4.4 ± 21.4%. Model "vancomycin_adult_C2" was closest both to measured vancomycin trough concentration and DOS model:%PE -4.5 ± 33.6% vs +4.2 ± 20.3%, RMSE 33.7 vs 20.6, Blandt-Altman bias +2.19 ± 6.17 (-9.9 - 14.3) vs -0.29 ± 3.25 (-6.7 - 6.1), resp. "#vancomycin_adult_C2" model produced largest%PE (-8.2%), RMSE (40.0) as well as Blandt-Altman bias +2.82 ± 6.76 (-10.4 - 16.1). The Pearson's R of predicted and measured vancomycin concentration, and of values predicted by WIN and DOS models, varied from 0.5135 to 0.5854, P<0.0001 and from 0.7869 to 0.8462, P<0.0001, resp. CONCLUSIONS: Three Windows vancomycin models and one DOS model in the Mw\Pharm software were compared. The best outcomes, i.e. lowest%PE, RMSE and highest Pearson's R, were reached with "vancomycin_adult_C2" model.

Monitoring topiramate concentrations at delivery and during lactation.

OBJECTIVE: To determine transplacental passage of topiramate and its transport to colostrum, mature maternal milk and breastfed infants, we examined data from 27 women treated with topiramate from 2004 to 2020. METHODS: In this cohort study, maternal serum, umbilical cord serum, milk and infant serum levels were measured by gas chromatography in the delivery subgroup, the colostrum subgroup (3-4 days postpartum) and the mature milk subgroup (7-30 days postpartum). Paired umbilical cord serum, maternal serum, breastfed infant serum, and milk levels were used to assess the ratios of umbilical cord/maternal serum, milk/maternal serum and infant/maternal serum levels. RESULTS: Topiramate levels varied from 1.0 to 7.1 mg/L in maternal serum and from 0.8 to 6.2 mg/L in umbilical cord serum, and the mean umbilical cord/maternal serum ratio was 0.93 ± 0.11. At 3-4 days after delivery, topiramate concentrations were 1.4-8.4 mg/L in maternal serum, 1.5-8.6 mg/L in milk and 0.3-4.4 mg/L in infant serum. The mean milk/maternal serum ratio was 0.99 ± 0.45, and the mean infant/maternal serum ratio was 0.25 ± 0.15. At 7-30 days after delivery, maternal serum levels varied from 1.9 to 9.7 mg/L, milk levels ranged from 2.3 to 10.6 mg/L and infant serum levels ranged from 0.3 to 6.5 mg/L. The mean milk/maternal serum ratio was 1.07 ± 0.31, and the mean infant/maternal serum ratio was 0.51 ± 0.27. CONCLUSIONS: We extended information about free transplacental passage of topiramate and its extensive transport to maternal milk with lower serum concentrations in breastfed infants in the largest group of patients ever reported to our knowledge. DATA AVAILABILITY STATEMENT: Authors declare that take full responsibility for the data, the analyses and interpretation, and the conduct of the research; that they have full access to all of the data; and that they have the right to publish all data. Authors were not participations in industry-sponsored research and corporate activities for evaluation of a manuscript.

Lamotrigine drug interactions in combination therapy and the influence of therapeutic drug monitoring on clinical outcomes in paediatric patients.

The aim was to study the impact of therapeutic drug monitoring (TDM) on paediatric patients on lamotrigine therapy and the evaluation of possible drug interactions, especially in triple antiepileptic drug combinations. During the period of 2001-2015, 1308 pre-dose samples were taken from 430 patients <15 years of age as part of routine TDM. Drug interactions were evaluated using calculation of lamotrigine clearance. Valproic acid decreased lamotrigine clearance by 54% in bitherapy, and by 21% in triple therapy with carbamazepine. Carbamazepine increased lamotrigine clearance by 191% in bitherapy. Levetiracetam and topiramate had no effect. The upper limit of lamotrigine therapeutic range (TR) was exceeded in 2% of cases in monotherapy, and in 6%-7% of cases in bi- or triple therapy. About 61% of plasma levels were found within the TR during 2001-2005, compared to 75% and 74% during 2006-2010 and 2011-2015, respectively. Adverse drug reactions (ADRs) were reported in 22 cases. Higher number of supratherapeutic levels in combination therapy led to a 3-fold increase in incidence of ADRs. Seizures occurred more often daily and monthly during 2001-2005 and in patients with three or four antiepileptic drugs in combination. Carbamazepine only partially compensated for the inhibitory effect of valproic acid. Lamotrigine clearance in monotherapy in children is similar to adults, but in polytherapy was found higher susceptibility to induction. A significantly higher number of supratherapeutic lamotrigine levels were found in combinations with valproate. Despite poor correlation with TR, both seizure frequency and ADRs declined after the implementation of TDM.

Lamotrigine Drug Interactions in Combination Therapy and the Influence of Therapeutic Drug Monitoring on Clinical Outcomes of Adult Patients.

BACKGROUND: The aim was to study the impact of therapeutic drug monitoring (TDM) on patients on lamotrigine (LTG) therapy and the evaluation of possible drug interactions, especially in triple antiepileptic drug combinations. METHODS: During the period of 2001-2014, 3118 predose samples were taken from 1137 patients >15 years of age as part of their routine TDM. Drug interactions were evaluated using calculation of LTG clearance (CL). RESULTS: Valproic acid (VPA) decreased LTG CL by 66% in bitherapy, and by 35% and 31% in triple therapy with carbamazepine (CBZ) and phenytoin (PHT), respectively. CBZ and PHT increased LTG CL by 52% and 96% in respective bitherapies but by 88% in triple therapy. Clonazepam, levetiracetam, and topiramate had no effect. The LTG therapeutic range (TR) was exceeded in 1% of cases in monotherapy, and in 4%-5% of cases in combination therapy. Only 54% of results were within the TR during 2001-2005, whereas 60%-62% were within the TR during 2006-2014. Adverse drug reactions (ADRs) were reported in 88 cases and occurred more frequently during TR during 2001-2005. Higher number of supratherapeutic levels in combination therapy led to a 3-fold higher incidence of ADR and poorer seizure control, as seizures occurred more often monthly (2.5%) or a few per year (41%) and fewer patients were seizure free (18%). Seizures occurred more often daily and monthly during the first period and in patients with 3 or 4 drugs in combination. CONCLUSIONS: A significantly higher number of supratherapeutic levels were found in combinations with VPA, despite lower doses of LTG. Hepatic enzyme inducers, such as CBZ and PHT only partially compensated for the inhibitory effect of VPA. Decrease of both the frequency of seizures and the incidence of ADRs after TDM implementation suggests that TDM may have given clinicians the opportunity to achieve more optimal patient treatment.

Validation of sparse sampling strategies to estimate cyclosporine A area under the concentration-time curve using either a specific radioimmunoassay or high-performance liquid chromatography method.

INTRODUCTION: Area under the concentration-time curve (AUC) has been advocated as a better parameter to monitor cyclosporine A than trough concentrations. Up to now, more than 100 equations to estimate AUC using a limited sampling strategy have been published, but not all have been validated. MATERIAL AND METHODS: Eight equations for AUC0-12h and two for AUC0-8h were validated. Concentrations of cyclosporine A were analyzed by high-performance liquid chromatography (HPLC) and a specific radioimmunoassay (RIA) method. Forty male renal transplant patients were included in the study. Blood samples were taken predose and at 0.5, 1, 1.5, 2, 3, 5, 8, and 12 hours after the morning dose when the patient was in steady state. The percentage prediction error (%pe) was used for an assessment of the performance of the equations. Mean %pe less than ± 15% and absolute %pe less than 30% in 95% of predictions were considered to be acceptable. Other possibilities such as %pe less than 25%, 20%, and 15% were also tested. RESULTS: Eight equations for AUC0-12h met the requirements using both assays, six in the HPLC set only and four in the RIA set only. The highest precision was obtained with AUC0-12h = 123.792 + 1.165*C1h + 3.021*C3h + 7.33*C8h proposed by de Mattos et al. The mean %pe was 1% ± 8% (-16 to 19) for HPLC (values given as mean ± standard deviation [range]) and -1 ± 5 (-17 to 10) for RIA. Mean absolute %pe was 7 ± 5 (0.0 to 19) for HPLC and 4 ± 4 (0.0 to 17) for RIA. For clinical use, the most suitable equation was AUC0-12h = 363.078 + 8.77*C1h + 3.07*C3h proposed by Wacke et al, which produced the second lowest %pe and used two sampling points in the period of 1 to 3 hours after dose. The mean %pe was -7 ± 10 (-25 to 25) for HPLC and 2.3 ± 6 (-10 to 17) for RIA. Mean absolute %pe was 10 ± 7 (0.4 to 25) for HPLC and 5 ± 4 (0.0 to 17) for RIA. The equation: AUC0-8h = 55.37 + 2.89*C0h + 1.08*C1h0.9*C2h + 2.23*C3h proposed by Foradori et al met the criteria with 95% of prediction with absolute %pe less than 15% in the HPLC set and 10% in the RIA set. CONCLUSION: The validation of equations is of major importance for prediction precision, whereas the analytical method for limited sampling strategy proposals had no influence. Because of the wide interassay variability, it is also important to know which analytical method was used for AUC calculation when interpreting the results.

The use of TDM data to assess the validity of defined daily doses of antiepileptics: a comparison between a Czech and Swedish University Hospital.

Prescribed daily doses (PDDs) of antiepileptic drugs (AED) (N03A ATC group) were recorded for drugs used in monotherapy or in combination therapy in the University Hospitals in Ostrava, Czech Republic and Huddinge, Sweden. Plasma concentrations were used as an indicator of the quality of treatment. PDDs were compared with the defined daily doses (DDDs) suggested by WHO in the ATC/DDD index 2005. Request and reply forms for therapeutic drug monitoring (TDM) were used as a source of mean PDDs. The study included 2,824 adult out- and in-patients in Huddinge treated from 1995 to 1999 and 1,268 out-patients treated in Ostrava from 1993 to 2004. The differences in PDD were tested by Student's t-test. Mean values of PDD were used when patients were examined more than once. Doses given in mono- and polytherapy were compared. Mean PDDs (in mg) in mono-/polytherapy in Huddinge and Ostrava were as follows (DDDs in parenthesis): carbamazepine 588/842 and 618/770 (1,000), clonazepam 3.0/2.5 and 3.4/2.4 (8), phenytoin 278/314 and 291/288 (300), gabapentin -/1,533 and -/921 (1,800), lamotrigine 228/228 and 216/195 (300), phenobarbital 90/75 and 183/117 (100), vigabatrin -/1,794 and -/1,259 (2,000), valproic acid 1,139/1,476 and 814/950 (1,500). The PDDs of most of the AEDs were lower than the DDDs with the exceptions for valproic acid (Huddinge, in polytherapy only), phenytoin, for which PDDs and DDDs were very close, and phenobarbital for which they were similar in Huddinge but higher in Ostrava. PDDs in monotherapy were only slightly lower than in combination therapy. Patients with plasma concentrations within the therapeutic range were usually treated with slightly higher doses than the remainder. In general, plasma concentrations tended to be in the low therapeutic range. The differences in PDDs between hospitals were significant in the case of valproic acid (P < 0.001), phenobarbital (except monotherapy within), vigabatrin, and gabapentin (P < 0.01), and carbamazepine (in monotherapy P < 0.05, polytherapy P < 0.01). Our data suggest that the DDDs of AEDs should be reconsidered as, in the majority of cases, they appear to be too high.

Therapeutic monitoring of antiepileptic drugs: a comparison between a Czech and a Swedish University Hospital.

Plasma concentrations obtained during routine therapeutic monitoring of antiepileptic drugs (AED) (N03A ATC group) were compared in patients treated with one or several AED in the University Hospitals in Ostrava, Czech Republic and Huddinge, Sweden. Request and reply forms for therapeutic drug monitoring (TDM) were used as a source of mean plasma concentrations (PC). The study included 2,824 adult out- and inpatients in Huddinge treated from 1995 to 1999 and 1,268 outpatients treated in Ostrava from 1993 to 2004. PC of valproic acid in Huddinge and all AED except clonazepam in Ostrava were analyzed with gas-liquid chromatography. Plasma concentrations of clonazepam in Ostrava and all AED except valproic acid in Huddinge were analyzed by HPLC. The differences in PC were tested by Student's t-test. Chi(2) method was used for the differences in the distribution of PC relative to the therapeutic window. The mean plasma concentrations generally reached the apparent therapeutic ranges but were below the range in the cases of phenytoin monotherapy in both hospitals, and clonazepam, phenobarbital and phenytoin in polytherapy in Ostrava. In monotherapy 33% of the analyses showed sub-therapeutic concentrations in Huddinge, compared to 38% in Ostrava. Eight percent of the analyses showed potentially toxic concentrations in Huddinge, but only 3% in Ostrava. The highest number of sub-therapeutic concentrations was detected for phenytoin in both hospitals: 59% in Huddinge, 78% in Ostrava. In polytherapy only slight differences between the hospitals were found. PC/dose ratios were significantly lower in polytherapy than in monotherapy for carbamazepine and valproic acid in both hospitals. In contrast a higher PC/dose ratio was found in polytherapy for phenytoin in both cohorts and for lamotrigine in Ostrava. Drug treatment of epilepsy in our two hospitals is surprisingly similar in terms of achieved plasma concentrations, in spite of socioeconomic and cultural differences between our two countries. This may be explained by the long experience with TDM in both hospitals, which has the inherent capacity to promote evidence based drug therapy.