Purpose: Donepezil, a drug frequently used to treat dementia, is mainly metabolized by cytochrome P450 2D6 (CYP2D6). This study investigated the relationships between CYP2D6 genotype and activity scores as well as predicted phenotype of plasma donepezil concentrations in 86 Thai dementia participants. Materials and Methods: CYP2D6 was genotyped using bead-chip technology (Luminex xTAG ® v.3). Steady-state trough plasma donepezil concentrations were measured using highperformance liquid chromatography. Results: Sixteen genotypes were found but the most frequent genotypes detected among our participants were CYP2D6*10/*10 (27.9%) and *1/*10 (26.7%). One-third of the participants had an activity score of 1.25 which predicted that they were normal metabolizers. The overall median (interquartile range) of plasma donepezil concentration was 51.20 (32.59-87.24) ng/mL. Normal metabolizers (NMs) had lower plasma donepezil concentrations compared to intermediate metabolizers (IMs) (41.15 (28.44-67.65) ng/mL vs 61.95 (35.25-97.00) ng/mL). Multivariate analysis showed that CYP2D6 activity score (r 2 = 0.50) and the predicted phenotype (independent of dose) could predict the plasma donepezil concentration (r 2 = 0.49). Conclusion: Plasma donepezil concentration in NMs was lower compared to IMs. Additional studies with larger sample size and use of next-generation sequencing as well as its outcomes are warranted to confirm the benefit of using pharmacogenetic-guided treatment for donepezil.
Relapsed or resistant lupus nephritis (LN) is considered a difficult-to-treat type of LN, and enteric-coated mycophenolate sodium (EC-MPS) has been used in this condition. Therapeutic drug monitoring using the area under the plasma mycophenolic acid concentration from 0 to 12 h postdose (MPA-AUC 0-12h ) ≥45 μg.h/ml is a useful approach to achieve the highest efficiency. This study assessed EC-MPS's pharmacokinetic (PK) and pharmacodynamic (PD) profiles and investigated an optimal level of the single time point of plasma MPA concentration.Nineteen biopsy-proven patients with class III/IV LN received 1440 mg/day of EC-MPS for 24 weeks. PK (maximum plasma MPA concentration [C max ], time to C max , and MPA-AUC 0-12h ) and PD (activity of inosine-5′-monophosphate dehydrogenase [IMPDH]) parameters were measured at weeks 2, 8, 16, and 24. We found that IMPDH activity decreased from baseline by 31-42% within 2-4 h after dosing, coinciding with the increased plasma MPA concentration. MPA-AUC 0-12h ≥45 μg.h/ml was best predicted by a single time point MPA concentration at C0.5, C2, C3, C4, and C8 (r 2 = 0.516, 0.514, 0.540, 0.611, and 0.719, respectively), independent of dose, albumin, urine protein/creatinine ratio, and urinalysis. The MPA-C0.5 cutoff of 2.03 g/ml yielded the highest overall sensitivity of 85% and specificity of 88.2% in predicting MPA-AUC 0-12h ≥45 μg.h/ml. A single timepoint of plasma MPA-C0.5 ≥2.03 μg/ml may help guide EC-MPS adjustment to achieve adequate drug exposure. Further study of EC-MPS used to validate this cutoff is warranted.
Study Highlights
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?Therapeutic drug monitoring (TDM) is crucial in lupus nephritis (LN) treated with mycophenolic acid (MPA), especially mycophenolate mofetil. The area under the plasma concentration-time curve of MPA from time 0 to 12 h
Background: Intraperitoneal (IP) cefazolin and ceftazidime during the short-dwell (≤ 2 h) automated exchange has been shown to provide adequate dialysate and plasma concentrations for up to 24 h in peritoneal dialysis (PD) patients without peritonitis. This study aimed to evaluate plasma and dialysate concentration of this novel IP cefazolin and ceftazidime regimen during the first 24 h in PD patients with peritonitis. Methods: Cefazolin and ceftazidime (2500 mg each) were added to in to a 5-L bag containing 2.5% of dextrose PD fluid which was placed on the warmer of PD cycling machine. Patients underwent five exchanges of 2-L PD fluid over 10 h by the PD cycling machine without last fill or additional dwell. Plasma samples and dialysate samples were collected over 24 h. Cefazolin and ceftazidime concentrations in plasma and dialysate were determined by high-performance liquid chromatography. Results: Seven PD patients with peritonitis participated in this study. Plasma cefazolin and ceftazidime levels increased substantially within the first few hours, peaked around 6–10 h, and sustained well above the target plasma concentrations (10 mg L−1 for cefazolin and 16 mg L−1 for ceftazidime) until 24 h. Dialysate cefazolin and ceftazidime levels were sustained above the target peritoneal concentrations (2 mg L−1 for cefazolin and 8 mg L−1 for ceftazidime) throughout the PD session except in some samples which the antibiotics levels were unusually low, probably from beta-lactamase activity. Conclusions: IP cefazolin and ceftazidime during the short-dwell automated exchange could provide adequate dialysate and plasma concentrations in peritonitis patients. This novel regimen is a promising regimen for peritonitis in PD patients.
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