No abstract

Aims The aims are to develop a population pharmacokinetic model of capecitabine (CAP) and its main metabolites after the oral administration of CAP in colorectal cancer patients with different polymorphisms of the ATP‐binding cassette (ABC) gene and a population pharmacokinetic/pharmacodynamic model capable of accounting for the neutropenic effects, and to optimize the dosing strategy based on the polymorphisms of the ABC gene and/or the administration regimen as a single agent or in combination. Methods Forty‐eight patients diagnosed with colorectal cancer were included, with 432 plasma levels of CAP, 5′‐desoxi‐5‐fluorouridine (5′‐DFUR) and 5‐fluorouracil (5‐FU), and 370 neutrophil observations. Capecitabine doses ranged from 1250 to 2500 mg/m2/24 h. Plasma measurements of CAP, 5′‐DFUR and 5‐FU were obtained at 1, 2 and 3 hours post administration. Neutrophil levels were measured between day 15 and day 24 post administration. Results The pharmacokinetic model incorporates oxaliplatin as a covariate on absorption lag time, rs6720173 (ABCG5 gene) on clearance of 5′‐DFUR (182% increase for mutated rs6720173) and rs2271862 (ABCA2 gene) on clearance of 5‐FU (184% increase for mutated rs2271862). System‐ (Circ0 = 3.54 × 109 cells/mL, MTT = 204 hours and γ = 6.0 × 10−2) and drug‐related (slope [SLP] = 3.1 × 10−2mL/mg). Co‐administration of oxaliplatin resulted in a 2.84‐fold increase in SLP. The predicted exposure thresholds to G3/4 neutropenia in combination and monotherapy were 26 and 70 mg·h/L, respectively. Conclusions The population pharmacokinetic/pharmacodynamic model characterized the time course of capecitabine and its metabolites in plasma. Dose recommendations of capecitabine in patients with mutated and wild allele for single nucleotide polymorphisms rs2271862 of ≤3000 and ≤2400 mg/m2/24 h in monotherapy and ≤1750 and ≤600 mg/m2/24 h in combination with oxaliplatin, respectively, have been proposed.

The probability that a PR will be implemented for a patient is related to the potential severity and the category of the identified ADE. Therefore, recommendations intended to improve effectiveness of pharmacotherapy or patient safety, and those with potential clinical consequences have a greater chance of being applied to a patient.

No abstract

No abstract

In patients with kidney transplants, the presence of acute tubular necrosis, together with the time the blood concentration of tacrolimus remained within the predetermined therapeutic interval, permitted the identification of patients with a higher probability of having an acute rejection episode during the first two weeks following the transplant.

No abstract

Background Tacrolimus, the basic component of immunosuppressive therapy to prevent allograft rejection after kidney transplantation, is characterised by great inter/intraindividual variability in its pharmacokinetics, partly explained by polymorphisms in metabolising enzymes. Purpose To determine the relationship between CYP3A5*3 polymorphism and intraindividual variability in tacrolimus pharmacokinetics to assess monitoring trends. Materials and methods Retrospective study in renal transplant recipients treated with tacrolimus, mycophenolate and methylprednisolone (May/2003-May/2011). Daily dose (DD), blood concentration (Cb, IMx and Architect immunoassay methods), monitoring date and CYP3A5*3 polymorphism (Real-Time PCR method) were recorded. To assess intraindividual variability, coefficient of variation of Cb/DD ratio (CVCp/DD) and % variation per day between consecutive Cb/DD (VCp/DD) were calculated. Stability was defined as the period in which the same DD was maintained for at least 3 months with Cb on target (5-10 ng/mL) and a VCp/DD<1%/day. Three post-transplant periods were studied (immediate (day 0-42), prestability and stability). Mean differences between groups were analysed by SPSS 18.0 (statistical significance if pt-Student<0.05). Results 38 patients were included, 95% (31 homozygous (HM), 5 heterozygous (HT)) achieved stability at follow-up (839±141 days). Times to stability were 40% higher in homozygous (HM: 367±65 vs HT: 258±117 days; p=0.067) and their variability was 25% greater in prestability time (CVCp/DD (%): HM: 33.40±4.88 vs HT: 26.73±3.47; p<0.05). No differences were observed in CVCp/DD in the immediate post-transplant period (HM: 30.28±3.51 vs HT: 32.52±8.92) or stability (HM: 19.88±3.42 vs HT: 19.28±10.3) or VCp/DD in any period (global values (%/day): 19.28±10.3, 1.04±0.16, 0.36±0.09). Once stability was achieved, time with the same DD and Cb on target was similar in both groups (HM: 160±33 vs HT: 136±83 days) and 200-300% higher than between consecutive determinations (57±6 vs 64±17 days). Conclusions CYP3A5*3 polymorphism increases, but does not fully explain, intraindividual variability in tacrolimus pharmacokinetics. Our data suggest that monitoring of patients can be extended to every 4-5 months from the 8th month (heterozygous) or the year post-transplant (homozygous) without compromising safety.