Cyclosporine A area-under-time-concentration-curve in rheumatologic patients after the first dose. Which of the sparse sampling strategies will predict the best?

OBJECTIVE: The aim of the present study was to validate the limited sampling strategies (LSS:s) for prediction of AUC of cyclosporine A (CsA) after the first dose in rheumatologic patients. METHODS: 22 patients suffering from rheumathoid arthritis, systemic lupus erythematodus, ankylosing spondylitis dermato(poly)myositis or seronegative spondylarthritis were treated with Neoral® (female/male: 11/3, mean ± SD: age 49 ± 14 y, body weight 75 ± 12 kg, height 166 ± 7 cm, dose 71 ± 25 mg, dose per kg 1.0 ± 0.3 mg/kg), or Consupren® (7/1, 78 ± 36, 175 ± 8, 82 ± 22, 1.1 ± 0.3). Two patients whose C12h were missing were excluded from the AUC0-12 calculation. Whole blood levels of CsA were analyzed with HPLC. Blood samples were collected at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours after taking the first dose. Altogether 115 LSS:s obtained from the literature were validated. A linear trapezoidal rule was used as a reference method. Mean percentage prediction error (%PE) < ± 15% and maximal one value of absolute %PE > 30% were considered to be acceptable. The root mean squared error (RMSE) was evaluated for equations that passed the criteria. RESULTS: The best performance with all values of the absolute %PE < 30% was found in three LSS:s for AUC0-12 and two for AUC0-8: AUC0-12 = 123.792 + 1.165 × C1h + 3.021 × C3h + 7.33 × C8h; 97.6 + 1.27 × C1h + 3.14 × C3h + 4.06 × C6h; or 124.3 + 1.34 × C1h - 0.16 × C2h + 3.27 × C3h + 3.96 × C6h; AUC0-8 = -19.8 + 1.99 × C2h + 2.38 × C4h + 3.15 × C6h or -22.4 + 2.51 × C2h + 5.49 × C6h. Validation criteria were further fulfilled in AUC0-12 = 24 + 3.66 × C0h + 2.11 × C1.5h + 4.54 × C4h or 0.2 + 2 × C2h + 10.2 × C6h; AUC0-8 = 55.37 + 2.89 × C0h + 1.08 × C1 + 0.9 × C2h + 2.23 × C3h; and AUC0-4 = -41 + 1.17 × C1h + 1.85 × C2h. Only one equation proposed for AUC0-6 did not pass the validation criteria. CONCLUSIONS: Equations validated for prediction of AUC0-12, AUC0-8 and AUC0-4 might be used for LSS:s of CsA independently of the length of treatment, indication, dosage or galenic formulation.

The possibility of using the specific RIA method for the area-under-time-concentration curve sparse sampling calculation of cyclosporin A despite a large post-dose overestimation.

OBJECTIVE: To find limited sampling strategies (LSS) for prediction of the real AUC using the RIA analytical method. METHOD: Blood samples of 40 male renal transplant patients taken pre-dose and after 0.5, 1, 1.5, 2, 3, 5, 8, and 12 h in the steady-state were analyzed with HPLC and the specific RIA method. I. Eight equations for AUC0-12 and one for AUC0-8 obtained from the literature, that produced the mean percentage prediction error (%PE) < ± 15% and absolute %PE < 30% in 95% of predictions, were analyzed for possibility to predict the real AUC of CsA. II. Multiple regression analysis (MRA) was provided for the AUC equation proposal. Patients were divided into two groups according to the AUC0-12. Group I was used for LSS : s proposals while Group II for validation. The bias and precision were expressed as %PE, r2 and RMSE. The relationship of %PE interassay and with LSS:s was expressed as Pearson correlation r. GraphPad InStatt Software was used for MRA and Pearson r calculation. RESULTS: None of the equations described in the literature predicts AUC of CsA proprietarily. Seven equations for AUC0-12 and five for AUC0-8 were proposed with MRA for prediction of real AUC from RIA values. CONCLUSIONS: LSS:s can moderate the interassay %PE in AUC of CsA. New patients should be tested with both RIA and HPLC for the level of overestimation. The conversion factors should be calculated for patients with an overestimation higher than 90%. Our equation 251.09 + 0.5195 × C1h + 4.926 × C3h or 196.13 + 4.526 Â× C0h + 2.089 × C1.5h for AUC0-12, and 171.80 + 0.4759 × C1h + 4.132 × C3h for AUC0-8 may be used in patients with medium or low RIA and HPLC differences. Repeated analysis with HPLC is thus suggested in cases with AUC:s results close to the lower or upper margin of the therapeutic window.

Significant discrepancy in cyclosporin A post-dose concentrations when analyzed with specific RIA and HPLC method.

C(2) or AUC sparse sampling methods are widely recommended for therapeutic monitoring of cyclosporin A (CsA). One additional reason for promoting the C(2) sampling time in place of commonly used C(0) is that the C(2) level may actually provide more accurate measurement of parent drug concentration by immunoassays, as lower portion of metabolites has been formed 2 hours post-dose than at the steady-state trough time point. HPLC and RIA whole blood levels of CsA and its main metabolites AM1, AM9 and AM4N were compared during 12 hours profile after chronic administration. 40 stable renal transplant male patients (age 49 +/- 6 years, body weight 76 +/- 7 kg) were treated with CsA (Sandimmun Neoral, Novartis s.r.o, Prague, Czech Republic) in doses 198 +/- 56 mg twice daily. Samples were collected in steady state (after 2 weeks of regular treatment regimen) as follows: pre-dose, 0.5, 1, 1.5, 2, 3, 5, 8 and 12 hours after dose. CsA concentrations were determined both specific RIA assay (Cyclo-Trac SP Whole, Dia Sorin) and HPLC method, where concentrations of metabolites AM1, AM9 and AM4N were simultaneously analyzed. The AUC(0-12) was calculated by the linear trapezoidal rule. The percentage prediction error defined as [(RIA value-HPLC value)/HPLC value] x 100 was used for estimation of differences. C(max), t(max), and C(avg) were compared using Student's t-test. RIA produced significantly higher CsA levels than HPLC method in the period of 0.5 - 5 hours after application. The greatest differences (43 - 56%) occurred between 1 and 3 hours after dose. AUC(0-12), C(max) a C(avg) calculated from RIA results were consequently significantly higher. Only t(max) remained unchanged. The ratio of metabolites/parent drug after CsA intake is decreasing but their absolute concentrations are significantly increasing. Mean levels at C(0)/C(2) were CsA-RIA 82/612, CsA-HPLC 89/425, AM1 121/179, AM9 4.1/81.4, AM4N 9.5/21.0 ng/ml. TDM using C(2) and AUC sparse sampling may cause misleading interpretation using both methods alternately for the same patient.

[Therapeutic plasma exchange in the treatment of the hereditary thrombotic thrombocytopenic purpura]. / Moznosti lécby plazmou u pacientu s hereditární formou trombotické trombocytopenické purpury.

BACKGROUND: Therapeutic plasma exchange is the treatment of choice for thrombotic thrombocytopenic purpura (TTP). METHODS AND RESULTS: Patients chronically treated with plasma exchange are frequently exposed to a large number of single plasma donors units, however successful clinical and laboratory improvement is generally achieved. Therapeutic plasma exchange significantly decreased mortality of this disease. Plasma treatment offers two possibilities--plasma infusion or plasma exchange and possibility of different plasma types. Cryoprecipitate-poor plasma was introduced as better form of FFP, however studies presented later did not confirm the therapeutic benefit. Quarantine FFP is widely used for patients with TTP in the Czech Republic; this type is tested frequently for negativity of human immunodeficiency virus, hepatitis B virus, hepatitis C virus and syphilis. Treatment with pathogen inactivated plasma (e.g., solvent detergent plasma, methylen-blue plasma, psoralen treated plasma or riboflavin treated plasma) is not frequently used in the Czech Republic. Authors present different plasma types and their experience with plasma treatment in seven patients with congenital form of TTP. CONCLUSIONS: In five patients therapeutic plasma exchange with quarantine fresh frozen plasma uas used. During each treatment 1.5 of plasma volume was exchanged. Two patients--teenagers were treated at the ex paediatric clinic with plasma infusion in regularly 2 weeks intervals.

Differences between prescribed daily doses and defined daily doses of antiepileptics--therapeutic drug monitoring as a marker of the quality of the treatment.

OBJECTIVE: Prescribed daily doses (PDDs) of antiepileptics (N03A ATC group) were recorded for drugs used in monotherapy or in combination therapy in the University Hospital in Ostrava, Czechia. Plasma levels were used as an indicator of the quality of treatment. METHOD: Request and reply forms for therapeutic drug monitoring (TDM) were used as a source of PDDs and plasma levels. The study included 1,144 in-patients examined in the period 1993 - 2004. The differences in PDD were tested by Mann-Whitney-U-test. ATC/DDD index 2005 was used. Doses given in mono- and polytherapy were compared. RESULTS: Median PDDs in samples within the therapeutic range (in mg) in mono-/polytherapy were as follows (DDDs in parenthesis): carbamazepine 600/800 (1,000), clonazepam 2.0/2.0 (8), phenytoin 300/300 (300), ethosuximide -/1000 (1,250), lamotrigine 250/200 (300), phenobarbital -/200 (100), primidone 500/625 (1,250), topiramate -/300 (300), valproic acid 750/1,000 (1,500). Median PDDs in polytherapy with antiepileptics not analyzed for TDM were: gabapentin 900 (1,800), levetiracetam 1,500 (1,500), vigabatrin 1,500 (2,000). CONCLUSIONS: PDDs in monotherapy were similar or slightly lower than in combination therapy with an exception for lamotrigine, NS. The differences were significant in carbamazepine, p < 0.0001, and valproic acid, p < 0.001. Patients with plasma levels within the therapeutic range were usually treated with similar or slightly higher doses than the remainder. In polytherapy the PDDs were similar to DDDs in carbamazepine, ethosuximide, phenytoin, and topiramate in samples within the therapeutic range when difference +/- 20 per cent was considered as acceptable PDD of levetiracetam was also similar to actual DDD. In general plasma levels tended to be below the therapeutic range. The differences between PDD and DDD of antiepileptics have to be taken into account especially when utilization of different drugs is compared.

[Consumption of antiepileptics in 1993-2004 using various methods]. / Spotreba antiepileptik v letech 1993-2004 s vyuzítím ruzných prístupo.

Drug utilization expresses the exposition of a drug in the relationship with determined population, certain time period, and specific socioeconomic background. The aim of this study was to compare the antiepileptic drug utilization (N03A) in the Czech Republic (CR) and in Ostrava University Hospital (FNsP). The sources of the data were I) wholesale data (SUKL, CR), II) prescriptions (UZIS, CR), III) request forms (FNsP), IV) request forms for therapeutic drug monitoring (FNsP). The utilization was expressed in DDD/TID (I, II), or in DDD/100 BD in neurological departments (III) on 5th or 4th level, resp. ATC/DDD index 2001, for levetiracetam 2004. Carbamazepine had the highest utilization that was increasing in the CR, while remaining high and constant in FNsP. The utilization of valproic acid is increasing. The number of patients shows greater prescription than utilization in DDD. The utilization of phenytoin was high in the CR, but diminished in FNsP. The number of patients was lower than expected. The utilization of barbiturates was considerable in the CR, but below the average in FNsP. The utilization of clonazepam and N03AX was increasing. The most important substance there was lamotrigin. The outcomes are in agreement with current recommendations. The utilization in FNsP and CR follows the same trend with a faster shift to newer drugs in FNsP.

[Comparison of the consumption of antiepileptic drugs in the Czech Republic, Scandinavia, and Australia]. / Porovnání spotreb antiepileptik v Ceské republice, Skandinávii a v Austrálii.

Long-term trends in utilization of antiepileptic drugs expressed in DDD/TID according to the 4th ATC level were studied. Wholesale data recorded from statistical yearbooks and the database of the State Institute for Drug Control (SUKL) were the source of data. The correlation between trends in the Czech Republic (CR) and the other countries was studied. The utilization was expressed in DDD/1000 inhabitants and day (DDD/TID). The lowest utilization of antiepileptics was in the Czech Republic, while highest in Norway (until 1994) and Finland (from 1995). The utilization of barbiturates is decreasing. The highest one was in Norway and CR. Hydantoins were the most widely utilized group in Australia, Sweden, and CR. Even though their utilization was lower in Finland and Norway, they were one of the most widely utilized groups there. The utilization of succnimide derivatives was very low and still decreases. Benzodiazepins were the most widely utilized group in Finland, until 1995 also in Australia, from 1996 in Norway. Their utilization increases. Even though the utilization of carboxamide derivatives was lower in CR and Australia, they belong to the second most widely utilized group there. Fatty acid derivatives were most widely utilized in Australia and Finland. Their utilization is lower, but increasing in CR. The utilization of N03AX has been increasing in the recent period in all countries. The utilization of antiepileptics in CR follows the trends in other countries, but on a lower level of DDD/TID.