Donatella Poz

TDM coupled with Bayesian forecasting should be considered an invaluable tool for optimizing vancomycin daily exposure in unstable critically ill patients

A randomized two-arm prospective study was planned to assess the role of therapeutic drug monitoring (TDM) coupled with a Bayesian approach in tailoring vancomycin dosages in unstable critically ill patients. Group A (n=16) had their regimen adjusted day-by-day according to TDM and Bayesian forecasting (D(a)); group B (n=16) had their regimen adjusted day-by-day according to Moellerings nomogram (D(M)). Blood samples were collected every 1-2 days to assess the trough and peak plasma concentrations. In group A, the tailored D(a) required for optimizing vancomycin exposure were considerably higher than the D(M) in 7/16 cases, and lower than the D(M) in 1/16 cases. In group B, standard D(M) caused under-treatment in 3/16 cases and over-treatment in 4/16 cases. Most of these patients concomitantly had some conditions that might have altered vancomycin disposition. The TDM-guided Bayesian-based approach should be considered an invaluable tool for clinicians to handle appropriately on real-time vancomycin therapy in critically ill patients.

Tamoxifen and its main metabolites serum and tissue concentrations in breast cancer women.

Because of a possible relationship between tamoxifen (T) concentrations and clinical effects, we initiated a preliminary investigation on serum and tissue concentrations of T and its main active metabolites, and 4-hydroxytamoxifen, in women with positive breast cancer estrogen receptor. One hundred forty-eight patients were studied: 80 were admitted for monitoring of therapeutic serum drug concentrations, 22 had tissue concentrations taken at surgery, and 46 patients had uterine mucosa levels measured at diagnostic hysteroscopy. Steady-state serum concentrations were reached after 1 month of continuous treatment, with desmethyltamoxifen being the highest represented derivative from the third week onward. There was no relationship between dose (in mg/kg body weight) and steady-state serum concentrations during therapeutic drug monitoring of patients. The highest tissue concentrations were observed in breast lymph-nodes, cancer tissue, and uterine mucosa. On the basis of these data, we speculate that T and its active metabolites may exert both a defensive role (ie, an obstacle to the diffusion of malignant cells through the local lymphatic system) and a harmful one (induction of uterine malignancies).

Optimisation of Vancomycin Regimen in Neutropenic Haematological Patients with Normal Renal Function

AbstractObjective: To assess the appropriateness, on a pharmacokinetic basis, of a twice-daily regimen of vancomycin 1g in neutropenic patients with normal renal function, a regimen frequently used in the empirical treatment of this patient group. The study also used a Bayesian pharmacokinetic approach to predict vancomycin concentrations in order to determine the optimal dosage frequency of the drug (two or four daily doses) in this population. Patients and Methods: Data were collected retrospectively as part of routine therapeutic drug monitoring (TDM) of vancomycin in 16 adult neutropenic patients. TDM of vancomycin peak (Cmax) and trough (Cmin) serum concentrations was performed after twice daily administration of vancomycin lg as a 1-hour intravenous infusion for 48 hours. According to TDM results (Cmin≥7 or <7 mg/L), the vancomycin regimen was individualised (total daily dose split into two or four divided doses) by means of a Bayesian-based pharmacokinetic computer programme. TDM was then repeated on day 7. Optimal Cmin were defined as with the range of 7 to 10 mg/L. Results: On day 3 of therapy, nine patients had subtherapeutic Cmin (3.97 ± 0.59 mg/L; range 2.98 to 4.95 mg/L) according to ahigh estimated creatinine clearance (CLcr 1.79 ± 0.49 ml/kg/min; range 1.39 to 2.79 ml/kg/min), and another three patients had Cmin <7 mg/L. On day 7, higher vancomycin Cmin were achieved (8.92 ± 2.87 mg/L) in the 12 patients in whom their total daily dose was split into four (Cmin were optimal in nine and supratherapeutic in three patients), despite no major differences in the total daily dosage of vancomycin (29.77 ± 5.89 vs 30.85 ± 6.68 mg/kg; p = 0.79) and CLcr (1.63 ± 0.43 vs 1.90 ± 0.45 ml/kg/min; p = 0.19) versus day 3. Dose-normalised results suggested large interindividual pharmacokinetic variability. Conclusion: Since the volume of distribution and/or clearance of vancomycin can be increased in patients with haematological malignancies and normal renal function, increasing the number of daily doses from two to four (with the same total daily dose) may increase t > MIC, an important determinant of vancomycin efficacy. However, because of interpatient variability, TDM of vancomycin is strongly recommended to individualise therapy in this subpopulation.

PHARMACOKINETIC PROFILE OF TWO DIFFERENT ADMINISTRATION SCHEMES OF TEICOPLANIN : SINGLE 400MG INTRAVENOUS DOSE VS DOUBLE-REFRACTED 200MG INTRAMUSCULAR DOSES IN HEALTHY VOLUNTEERS

AbstractObjective: To evaluate the pharmacokinetic appropriateness of a possible switch in dosing schedule for outpatients after hospital discharge, i.e. the bioequivalence of a single 400mg intravenous daily dose versus double-refracted 200mg intramuscular doses. Subjects and Methods: This study was conducted in 10 normal healthy volunteers using a two-way randomised, open-label, two-period crossover design. Each subject received two different drug regimens of teicoplanin: a single 400mg intravenous daily dose versus double daily refracted 200mg intramuscular doses. Teicoplanin serum concentrations were analysed by means of a fluorescence polarisation immunoassay system in samples collected for up to 72 hours after each regimen. Pharmacokinetic evaluations were performed by means of a 3-compartment open model with first-order elimination using the WinNonlin pharmacokinetic software package. Results: Teicoplanin peak serum concentrations were 97.96 ± 23.49 mg/L, 3.47 ± 1.00 mg/L and 6.99 ± 1.52 mg/L after a single 400mg intravenous dose, and after the first and second intramuscular administrations, respectively. The trough level at 24 hours (C24)was 4.55 ± 1.04 mg/L after the 400mg intravenous dose, and 6.67 ± 1.75 mg/L after double 200mg intramuscular doses. The ratio between C24 intramuscular and intravenous treatment was 1.46 ± 0.17. Total body exposure (AUCo-∞) was 474.22 ± 111.77 mg/L · h post-intravenous dose, and 424.84 ± 113.53 mg/L · h post-intramuscular doses. Intramuscular bioavailability suggested substantial bioequivalence with intravenous administration (89.58 ± 14.35%). Dose-normalised data indicated that the intersubject variability was mainly related to interindividual differences in bodyweight. Conclusion: These findings indicated that a total daily dosage of teicoplanin 400mg administered in two refracted doses by the intramuscular route could produce steady-state trough levels that are even higher than those achievable after once-daily intravenous administration during maintenance treatment. Since the time during which the serum concentration persists above MIC is actually thought to be a possible major determinant for the outcome of treatment with glycopeptides, this intramuscular schedule could enhance the pharmacokinetic exposure to teicoplanin. Therefore, a timely conversion from intravenous to intramuscular therapy in outpatients at the moment of hospital discharge (changing therapy from 400mg intravenously once daily to 200mg intramuscularly twice daily) may be reliably proposed, allowing better compliance without reducing efficacy.

Oral and intravenous disposition of cyclosporine in psoriatic patients.

After informed consent was obtained and with the approval of the Local Ethical Committee, cyclosporine A (CsA) kinetics was studied in 63 psoriatic patients by giving them 2.5 mg/kg CsA orally. In order to calculate oral bioavailability, F, 22 patients were given the same dose i.v. Values of the calculated kinetic parameters were oral F = 22–63%; half-life, t1/2β, = 11.05–13.70 h; volume of distribution, Vd, = 4.00–5.02/L/kg; total body clearance, Cl, = 4.25–4.14 ml/min/kg. The area under the blood concentration time curve was more closely related to the dose (r = 0.66) than were trough levels (r = 0.52). No significant relationship was observed between the kinetic parameters studied and the age of the patient.