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  • 1
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    Fast and reliable quantification of busulfan in blood plasma using two-channel liquid chromatography tandem mass spectrometry: Validation of assay performance in the presence of drug formulation excipients
    Elsevier BV ; 2021
    In:  Journal of Pharmaceutical and Biomedical Analysis Vol. 203 ( 2021-09), p. 114216-
    Details
    In: Journal of Pharmaceutical and Biomedical Analysis, Elsevier BV, Vol. 203 ( 2021-09), p. 114216-
    Type of Medium: Online Resource
    ISSN: 0731-7085
    URL: Article
    DOI: 10.1016/j.jpba.2021.114216
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 1491820-1
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  • 2
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    Longitudinal Study of Tacrolimus in Lymphocytes During the First Year After Kidney Transplantation
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Therapeutic Drug Monitoring Vol. 40, No. 5 ( 2018-10), p. 558-566
    Details
    In: Therapeutic Drug Monitoring, Ovid Technologies (Wolters Kluwer Health), Vol. 40, No. 5 ( 2018-10), p. 558-566
    Abstract: Tacrolimus (TAC) is an immunosuppressive drug used after organ transplantation. Dosing is adjusted using whole blood (WB-TAC) measurements. Patients within the therapeutic WB-TAC window still experience rejections and adverse effects. Alternative monitoring methods are therefore warranted. The authors developed a method for measuring TAC in peripheral blood mononuclear cell (PBMC) isolates (PBMC-TAC) and performed a pharmacokinetic study in a cohort of kidney transplant patients during the first year after transplantation. Methods: PBMCs were isolated from whole blood by gradient centrifugation. After methanol-based extraction, liquid chromatography with tandem mass spectrometry was used to determine TAC in the extract. PBMC-TAC was normalized to the number of cells and alternatively to the protein amount in cells. Predose and postdose (1.5 hours) samples from kidney transplant patients were collected at 1 week, 6 weeks, and 1 year after transplantation. WB-TAC was measured using immunoassay. Results: The PBMC-TAC assay fulfilled the validation criteria of the European Medicines Agency guidelines. Twenty-nine patients completed the study. Predose PBMC-TAC was (median) 23 (1 week), 33 (6 weeks), and 27 pg/10 6 cells (1 year). Postdose PBMC-TAC was 44, 30, and 27 pg/10 6 cells at 1 week, 6 weeks, and 1 year after transplantation, respectively. Predose WB-TAC (median) was 5.0, 6.0, and 5.4 mcg/L, and postdose WB-TAC was 10.5, 8.3, and 9.1 mcg/L, respectively, at 1 week, 6 weeks, and 1 year after transplantation. Whole blood and PBMC-TAC correlated at all timepoints (rho 0.40–0.82, P 〈 0.05) except before dosage at 6 weeks. PBMC-TAC normalized to the number of cells, and the amount of protein was modestly correlated (rho 0.36–0.81, P 〈 0.056). Conclusions: The correlation between WB-TAC and PBMC-TAC is modest during the first-year posttransplantation. Normalization of PBMC-TAC to cells or protein may yield different results. PBMC-TAC is increased 1.5 hours after dose at 1 week after transplantation, but not after 6 weeks or 1 year, indicating altered distribution kinetics.
    Type of Medium: Online Resource
    ISSN: 0163-4356
    URL: Article
    DOI: 10.1097/FTD.0000000000000539
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 2048919-5
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  • 3
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    Tacrolimus Can Be Reliably Measured With Volumetric Absorptive Capillary Microsampling Throughout the Dose Interval in Renal Transplant Recipients
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Therapeutic Drug Monitoring Vol. 41, No. 5 ( 2019-10), p. 607-614
    Details
    In: Therapeutic Drug Monitoring, Ovid Technologies (Wolters Kluwer Health), Vol. 41, No. 5 ( 2019-10), p. 607-614
    Abstract: Therapeutic drug monitoring is standard practice for the immunosuppressant tacrolimus (Tac). Venous blood sampling at outpatient clinics is time-consuming and impractical with regard to obtaining trough concentrations on clinical visit days. Home-based blood sampling may be patient friendly and pave the way for limited sampling strategies for the prediction of total drug exposure. The aim was to establish a Tac assay for dried capillary microsamples, ensuring reliable measurements during the full dose interval in renal transplant recipients. Methods: An assay based on volumetric absorptive microsampling and liquid chromatography tandem mass spectrometry was validated. The agreement between capillary microsamples and liquid venous samples was investigated in stable renal recipients on twice-daily Tac dosing. Sampling throughout the 12-hour dose interval was examined at 2 separate days, at least 1 week apart, for each participant. Two sets of samples were obtained at each time point, one delivered directly to the laboratory and one sent through mail. Results: Twenty-seven renal transplant recipients were included, of whom 26 were investigated twice. Tac was efficiently extracted from the dried microsamples (mean recovery 94%–103%). The between-series mean accuracy was 88%–98% with coefficients of variation ≤5.0% (≤11% at the lower limit of quantification), measurement range 0.70–60 mcg/L. The mean difference between parallel microsamples was 5%–7%. Overall, the mean differences between dried microsamples and liquid samples were −3.1% when mailed (n = 679) and −4.2% when directly delivered (n = 682). Less than 8% were outside ±20%. The microsamples were stable for 1 month at ambient temperature. Conclusions: The microsample method demonstrated acceptable performance. Tac concentrations can be reliably quantified throughout the dose interval by using volumetric absorptive microsampling in renal transplant recipients, and the results are not influenced by postal shipment.
    Type of Medium: Online Resource
    ISSN: 0163-4356
    URL: Article
    DOI: 10.1097/FTD.0000000000000655
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 2048919-5
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  • 4
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    Mycophenolate pharmacokinetics and inosine monophosphate dehydrogenase activity in liver transplant recipients with an emphasis on therapeutic drug monitoring
    Informa UK Limited ; 2013
    In:  Scandinavian Journal of Clinical and Laboratory Investigation Vol. 73, No. 2 ( 2013-03), p. 117-124
    Details
    In: Scandinavian Journal of Clinical and Laboratory Investigation, Informa UK Limited, Vol. 73, No. 2 ( 2013-03), p. 117-124
    Type of Medium: Online Resource
    ISSN: 0036-5513 , 1502-7686
    URL: Article
    DOI: 10.3109/00365513.2012.745947
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2013
    detail.hit.zdb_id: 1492634-9
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  • 5
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    Atorvastatin Metabolite Pattern in Skeletal Muscle and Blood from Patients with Coronary Heart Disease and Statin‐Associated Muscle Symptoms
    Wiley ; 2023
    In:  Clinical Pharmacology & Therapeutics Vol. 113, No. 4 ( 2023-04), p. 887-895
    Details
    In: Clinical Pharmacology & Therapeutics, Wiley, Vol. 113, No. 4 ( 2023-04), p. 887-895
    Abstract: Self‐perceived statin‐associated muscle symptoms (SAMS) are prevalent, but only a minority is drug‐dependent. Diagnostic biomarkers are not yet identified. The local statin exposure in skeletal muscle tissue may correlate to the adverse effects. We aimed to determine whether atorvastatin metabolites in blood reflect the corresponding metabolite levels in skeletal muscle, and whether genetic variants of statin transporters modulate this relationship. We also addressed atorvastatin metabolites as potential objective biomarkers of SAMS. Muscle symptoms were examined in patients with coronary disease and self‐perceived SAMS during 7 weeks of double‐blinded treatment with atorvastatin 40 mg/day and placebo in randomized order. A subset of 12 patients individually identified with more muscle symptoms on atorvastatin than placebo (confirmed SAMS) and 15 patients with no difference in muscle symptom intensity (non‐SAMS) attended the present follow‐up study. All received 7 weeks of treatment with atorvastatin 40 mg/day followed by 8 weeks without statins. Biopsies from the quadriceps muscle and blood plasma were collected after each treatment period. Strong correlations (rho 〉  0.7) between muscle and blood plasma concentrations were found for most atorvastatin metabolites. The impact of the SLCO1B1 c.521T 〉 C (rs4149056) gene variant on atorvastatin's systemic pharmacokinetics was translated into muscle tissue. The SLCO2B1 c.395G 〉 A (rs12422149) variant did not modulate the accumulation of atorvastatin metabolites in muscle tissue. Atorvastatin pharmacokinetics in patients with confirmed SAMS were not different from patients with non‐SAMS. In conclusion, atorvastatin metabolite levels in skeletal muscle and plasma are strongly correlated, implying that plasma measurements are suitable proxies of atorvastatin exposure in muscle tissue. The relationship between atorvastatin metabolites in plasma and SAMS deserves further investigation.
    Type of Medium: Online Resource
    ISSN: 0009-9236 , 1532-6535
    URL: Issue
    URL: Article
    DOI: 10.1002/cpt.v113.4
    DOI: 10.1002/cpt.2844
    RVK:
    XA 36900
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2040184-X
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  • 6
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    In vitro assessments predict that CYP3A4 contributes to a greater extent than CYP3A5 to prednisolone clearance
    Wiley ; 2021
    In:  Basic & Clinical Pharmacology & Toxicology Vol. 129, No. 6 ( 2021-12), p. 427-436
    Details
    In: Basic & Clinical Pharmacology & Toxicology, Wiley, Vol. 129, No. 6 ( 2021-12), p. 427-436
    Abstract: Because several steroid hormones are metabolized to their respective 6β‐hydroxy forms by CYP3A4 and CYP3A5, these isoenzymes have been assumed to metabolize the immunosuppressive drug prednisolone, with conflicting results in the literature with respect to their relative importance. A direct study of the metabolism of prednisolone by microsomal CYP3A4 and CYP3A5 is missing. The aim of this in vitro study was to investigate the relative importance of recombinant CYP3A4 and recombinant CYP3A5 in the metabolism of prednisolone and to compare the extent of formation of 6β‐OH‐prednisolone by the two enzymes. Through in vitro incubations using rCYP3A4 and rCYP3A5 enzymes, intrinsic clearance (CL int ) of prednisolone was determined by the substrate depletion approach. Formation of the metabolite 6β‐OH‐prednisolone by rCYP3A4 and rCYP3A5, respectively, was compared. Prednisolone concentrations were measured, and its metabolite 6β‐OH‐prednisolone was identified using a HPLC‐MS/MS in‐house method. CL int for prednisolone by rCYP3A5 was less than 26% relative to rCYP3A4. Formation of 6β‐OH‐prednisolone by rCYP3A5 was less than 11% relative to rCYP3A4. The study indicates that 6β‐hydroxylation of prednisolone assessed in vitro in recombinant CYP enzymes depends on rCYP3A4 rather than rCYP3A5 and that CYP3A5 may be responsible for the formation of other prednisolone metabolite(s) in addition to 6β‐OH‐prednisolone.
    Type of Medium: Online Resource
    ISSN: 1742-7835 , 1742-7843
    URL: Issue
    URL: Article
    DOI: 10.1111/bcpt.v129.6
    DOI: 10.1111/bcpt.13645
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2151592-X
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  • 7
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    Pharmacodynamic assessment of mycophenolic acid in resting and activated target cell population during the first year after renal transplantation
    Wiley ; 2020
    In:  British Journal of Clinical Pharmacology Vol. 86, No. 6 ( 2020-06), p. 1100-1112
    Details
    In: British Journal of Clinical Pharmacology, Wiley, Vol. 86, No. 6 ( 2020-06), p. 1100-1112
    Abstract: To explore the pharmacodynamics of mycophenolic acid (MPA) through inosine monophosphate dehydrogenase (IMPDH) capacity measurement and purine levels in peripheral blood mononuclear cells (PBMC) longitudinally during the first year after renal transplantation (TX). Methods PBMC were isolated from renal recipients 0–4 days prior to and 6–9 days, 5–7 weeks and 1 year after TX (before and 1.5 hours after dose). IMPDH capacity and purine (guanine and adenine) levels were measured in stimulated and nonstimulated PBMC. Results Twenty‐nine patients completed the follow‐up period, of whom 24 received MPA. In stimulated PBMC, the IMPDH capacity (pmol 10 −6 cells min −1 ) was median (interquartile range) 127 (95.8–147) before TX and thereafter 44.9 (19.2–93.2) predose and 12.1 (4.64–23.6) 1.5 hours postdose across study days after TX. The corresponding IMPDH capacity in nonstimulated PBMC was 5.71 (3.79–6.93), 3.35 (2.31–5.62) and 2.71 (1.38–4.08), respectively. Predose IMPDH capacity in nonstimulated PBMC increased with time, reaching pre‐TX values at 1 year. In stimulated PBMC, both purines were reduced before (median 39% reduction across days after TX) and after (69% reduction) dose compared to before TX. No alteration in the purine levels was observed in nonstimulated PBMC. Patients needing dose reductions during the first year had lower pre‐dose IMPDH capacity in nonstimulated PBMC (1.87 vs 3.00 pmol 10 −6 cells min −1 , P = .049) at 6–9 days. Conclusion The inhibitory effect of MPA was stronger in stimulated PBMC. Nonstimulated PBMC became less sensitive to MPA during the first year after TX. Early IMPDH capacity appeared to be predictive of dose reductions.
    Type of Medium: Online Resource
    ISSN: 0306-5251 , 1365-2125
    URL: Issue
    URL: Article
    DOI: 10.1111/bcp.v86.6
    DOI: 10.1111/bcp.14218
    RVK:
    XA 33650
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 1498142-7
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  • 8
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    Prednisolone and Prednisone Pharmacokinetics in Adult Renal Transplant Recipients
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Therapeutic Drug Monitoring Vol. 43, No. 2 ( 2021-04), p. 247-255
    Details
    In: Therapeutic Drug Monitoring, Ovid Technologies (Wolters Kluwer Health), Vol. 43, No. 2 ( 2021-04), p. 247-255
    Abstract: Prednisolone (PL) is a standard component of most immunosuppressive protocols after solid organ transplantation (Tx). Adverse effects are frequent and well known. The aim of this study was to characterize the pharmacokinetics (PKs) of PL and prednisone (PN), including cortisol (CL) and cortisone (CN) profiles, after PL treatment in renal Tx recipients in the early post-Tx phase. Methods: This single-center, prospective, observational study included stable renal Tx recipients, 〉 18 years of age, and in the early postengraftment phase. Blood samples were obtained predose and during a 24-hour dose interval [n = 26 samples per area under the curve (AUC 0–24 )], within the first 8 weeks post-Tx. PL, PN, CL, and CN concentrations were measured using high-performance liquid chromatography−tandem mass spectrometry. Results: In renal Tx recipients (n = 28), our results indicated a relatively high PL exposure [median, range AUC 0–24 = 3821 (2232–5382) mcg h/L], paralleled by strong suppression of endogenous CL profile, demonstrated by a low CL evening-to-morning ratio [median, range 11 (3–47)%] . A negative correlation ( r = −0.83) between PL AUC 0–24 and morning CL levels was observed. The best single PK variable to predict PL AUC 0–24 was PL C 6 ( r 2 = 0.82). An algorithm based on 3 PK sampling time points: trough, 2, and 4 hours after PL dosing, predicted PL AUC 0–24 with a low percentage prediction error (PPE = 5.2 ± 1.5%) and a good correlation of determination ( r 2 = 0.91). PL AUC 0–24 varied 3-fold among study participants, whereas CL AUC 0–24 varied by 18-fold. Conclusions: The large interindividual variability in both PL exposure and suppression of endogenous CL implies a possible role for therapeutic drug monitoring. An abbreviated profile within the first 4 hours after PL dosing provides a good prediction of PL exposure in renal Tx recipients. The strong negative correlation between PL AUC 0–24 and morning CL levels suggests a possible surrogate marker for drug exposure for further evaluation.
    Type of Medium: Online Resource
    ISSN: 0163-4356
    URL: Article
    DOI: 10.1097/FTD.0000000000000835
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
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  • 9
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    Monitoring Simvastatin Adherence in Patients With Coronary Heart Disease: A Proof-of-Concept Study Based on Pharmacokinetic Measurements in Blood Plasma
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Therapeutic Drug Monitoring Vol. 44, No. 4 ( 2022-08), p. 558-567
    Details
    In: Therapeutic Drug Monitoring, Ovid Technologies (Wolters Kluwer Health), Vol. 44, No. 4 ( 2022-08), p. 558-567
    Abstract: Poor statin adherence remains a public health concern associated with adverse outcomes. We evaluated the use of pharmacokinetic measurements to monitor adherence to simvastatin in patients with coronary heart disease (CHD). Methods: Eighteen patients with CHD taking an evening dose of simvastatin 20 mg (n = 7), 40 mg (n = 5), or 80 mg (n = 6) were examined at steady-state pharmacokinetics. Ten patients were instructed to interrupt simvastatin dosing and return for blood sampling for the subsequent 3 days. Dose-normalized plasma concentrations of simvastatin lactone and simvastatin acid and the sum of the 2 were evaluated to discriminate between adherent dosing and dose omission. Bioanalytical quantification was performed using liquid chromatography–tandem mass spectrometry. Results: A simvastatin acid cutoff of 1.0 × 10 −2 nmol −1 ·L −1 ·mg −1 identified 100% of those omitting 2 doses and 60% of those omitting a single dose. Simvastatin acid showed superior ability to discriminate dose omission, as well as the best agreement between samples handled at ambient and cool temperatures (median deviation 3.5%; interquartile range −2.5% to 13%). The cutoff for a morning dose schedule, with a similar ability to discriminate, was estimated at 2.0 × 10 −3 nmol −1 ·L −1 ·mg −1 . Conclusions: The present method discriminated between adherence and reduced adherence to simvastatin therapy in patients with CHD. Sample handling is feasible for routine practice, and the assessment of adherence can be performed by direct measurement of simvastatin acid in a blood sample, according to defined cutoff values. Further studies validating the cutoff value and utility for clinical application are encouraged.
    Type of Medium: Online Resource
    ISSN: 0163-4356
    URL: Article
    DOI: 10.1097/FTD.0000000000000992
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
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  • 10
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    A Method for Direct Monitoring of Atorvastatin Adherence in Cardiovascular Disease Prevention: Quantification of the Total Exposure to Parent Drug and Major Metabolites Using 2-Channel Chromatography and Tandem Mass Spectrometry
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Therapeutic Drug Monitoring Vol. 41, No. 1 ( 2019-02), p. 19-28
    Details
    In: Therapeutic Drug Monitoring, Ovid Technologies (Wolters Kluwer Health), Vol. 41, No. 1 ( 2019-02), p. 19-28
    Abstract: Low adherence to statin therapy remains a public health concern associated with poor prognosis in cardiovascular disease patients. A feasible method for statin adherence monitoring in clinical practice has yet to be developed. In this article, we describe a novel method designed for the direct monitoring of atorvastatin adherence based on the sum of parent drug and major metabolites in blood samples. Methods: Acid and lactone forms of atorvastatin, 2-OH-atorvastatin, and 4-OH-atorvastatin were assayed. Plasma proteins were precipitated with an acidified mixture of methanol, acetonitrile, and aqueous zinc sulfate, and the supernatant was analyzed with 2-channel reversed-phase chromatography coupled to tandem mass spectrometry. Assay validation was performed according to the guidelines provided by the European Medicines Agency and the US Food and Drug Administration. Results: The effective run time was 1 minute and 45 seconds per sample. Mean accuracy ranged from 92% to 110%, and coefficients of variation were ≤8.1% over the measurement ranges for individual compounds. The sum of acids and corresponding lactones was stable in clinical plasma samples kept at ambient temperature for up to 6 days after blood sampling (mean sum within 96.6%–101% of baseline). Conclusions A fast and reliable assay for the quantification of atorvastatin and its 5 major metabolites in clinical blood samples is reported. Limitations of preanalytical stability were solved using the sum of the acid and lactone forms. The assay is feasible for implementation in clinical practice, and the sum of parent drug and metabolites may be used for direct monitoring of atorvastatin adherence.
    Type of Medium: Online Resource
    ISSN: 0163-4356
    URL: Article
    DOI: 10.1097/FTD.0000000000000578
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 2048919-5
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