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14 pages, 2129 KiB

Open AccessArticle

Population Pharmacokinetic Analysis of Pazopanib in Patients and Determination of Target AUC

by Agustos Cetin Ozbey, David Combarel, Vianney Poinsignon, Christine Lovera, Esma Saada, Olivier Mir and Angelo Paci

Pharmaceuticals 2021, 14(9), 927; https://doi.org/10.3390/ph14090927 - 15 Sep 2021

Cited by 6 | Viewed by 2948

Abstract

Pazopanib is a potent multi-targeted kinase inhibitor approved for the treatment of advanced renal cell carcinoma and soft tissue sarcoma. The pharmacokinetics of pazopanib is characterized by a significant inter- and intra-patient variability and a target through plasma concentration of 20.5 mg·L⁻¹ [...] Read more.

Pazopanib is a potent multi-targeted kinase inhibitor approved for the treatment of advanced renal cell carcinoma and soft tissue sarcoma. The pharmacokinetics of pazopanib is characterized by a significant inter- and intra-patient variability and a target through plasma concentration of 20.5 mg·L⁻¹. However, routine monitoring of trough plasma concentrations at fixed hours is difficult in daily practice. Herein, we aimed to characterize the pharmacokinetic (PK) profile of pazopanib and to identify a target area under the curve (AUC) more easily extrapolated from blood samples obtained at various timings after drug intake. A population pharmacokinetic (popPK) model was constructed to analyze pazopanib PK and to estimate the pazopanib clearance of a patient regardless of the time of sampling. Data from the therapeutic drug monitoring (TDM) of patients with cancer at Institute Gustave Roussy and a clinical study (phase I/II) that evaluates the tolerance to pazopanib were used. From the individual clearance, it is then possible to obtain the patient’s AUC. A target AUC for maximum efficacy and minimum side effects of 750 mg·h·L⁻¹ was determined. The comparison of the estimated AUC with the target AUC would enable us to determine whether plasma exposure is adequate or whether it would be necessary to propose therapeutic adjustments. Full article

(This article belongs to the Special Issue Precision Medicine in Oncology: Controlling the Pharmacokinetics Variability)

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17 pages, 2060 KiB

Open AccessArticle

Association between Olaparib Exposure and Early Toxicity in BRCA-Mutated Ovarian Cancer Patients: Results from a Retrospective Multicenter Study

by Maud Velev, Alicja Puszkiel, Benoit Blanchet, Sixtine de Percin, Nicolas Delanoy, Jacques Medioni, Claire Gervais, David Balakirouchenane, Nihel Khoudour, Patricia Pautier, Alexandra Leary, Zahra Ajgal, Laure Hirsch, François Goldwasser, Jerome Alexandre and Guillaume Beinse

Pharmaceuticals 2021, 14(8), 804; https://doi.org/10.3390/ph14080804 - 16 Aug 2021

Cited by 16 | Viewed by 3544

Abstract

Factors associated with olaparib toxicity remain unknown in ovarian cancer patients. The large inter-individual variability in olaparib pharmacokinetics could contribute to the onset of early significant adverse events (SAE). We aimed to retrospectively analyze the pharmacokinetic/pharmacodynamic relationship for toxicity in ovarian cancer patients [...] Read more.

Factors associated with olaparib toxicity remain unknown in ovarian cancer patients. The large inter-individual variability in olaparib pharmacokinetics could contribute to the onset of early significant adverse events (SAE). We aimed to retrospectively analyze the pharmacokinetic/pharmacodynamic relationship for toxicity in ovarian cancer patients from “real life” data. The clinical endpoint was the onset of SAE (grade III/IV toxicity or dose reduction/discontinuation). Plasma olaparib concentration was assayed using liquid chromatography at any time over the dosing interval. Trough concentrations (CminPred) were estimated using a population pharmacokinetic model. The association between toxicity and clinical characteristics or CminPred was assessed by logistic regression and non-parametric statistical tests. Twenty-seven patients were included, among whom 13 (48%) experienced SAE during the first six months of treatment. Olaparib CminPred was the only covariate significantly associated with increased risk of SAE onset (odds ratio = 1.31, 95%CI = [1.10; 1.57], for each additional 1000 ng/mL). The ROC curve identified a threshold of CminPred = 2500 ng/mL for prediction of SAE onset (sensitivity/specificity 0.62 and 1.00, respectively). This study highlights a significant association between olaparib plasma exposure and SAE onset and identified the threshold of 2500 ng/mL trough concentration as potentially useful to guide dose adjustment in ovarian cancer patients. Full article

(This article belongs to the Special Issue Precision Medicine in Oncology: Controlling the Pharmacokinetics Variability)

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20 pages, 2517 KiB

Open AccessArticle

Cross-Validation of a Multiplex LC-MS/MS Method for Assaying mAbs Plasma Levels in Patients with Cancer: A GPCO-UNICANCER Study

by Clémence Marin, Nihel Khoudour, Aurélien Millet, Dorothée Lebert, Pauline Bros, Fabienne Thomas, David Ternant, Bruno Lacarelle, Jérôme Guitton, Joseph Ciccolini and Benoit Blanchet

Pharmaceuticals 2021, 14(8), 796; https://doi.org/10.3390/ph14080796 - 12 Aug 2021

Cited by 17 | Viewed by 4887

Abstract

Background: Different liquid chromatography tandem mass spectrometry (LC–MS/MS) methods have been published for quantification of monoclonal antibodies (mAbs) in plasma but thus far none allowed the simultaneous quantification of several mAbs, including immune checkpoint inhibitors. We developed and validated an original multiplex LC–MS/MS [...] Read more.

Background: Different liquid chromatography tandem mass spectrometry (LC–MS/MS) methods have been published for quantification of monoclonal antibodies (mAbs) in plasma but thus far none allowed the simultaneous quantification of several mAbs, including immune checkpoint inhibitors. We developed and validated an original multiplex LC–MS/MS method using a ready-to-use kit to simultaneously assay 7 mAbs (i.e., bevacizumab, cetuximab, ipilimumab, nivolumab, pembrolizumab, rituximab and trastuzumab) in plasma. This method was next cross-validated with respective reference methods (ELISA or LC–MS/MS). Methods: The mAbXmise kit was used for mAb extraction and full-length stable-isotope-labeled antibodies as internal standards. The LC–MS/MS method was fully validated following current EMA guidelines. Each cross validation between reference methods and ours included 16–28 plasma samples from cancer patients. Results: The method was linear from 2 to 100 µg/mL for all mAbs. Inter- and intra-assay precision was <14.6% and accuracy was 90.1–111.1%. The mean absolute bias of measured concentrations between multiplex and reference methods was 10.6% (range 3.0–19.9%). Conclusions: We developed and cross-validated a simple, accurate and precise method that allows the assay of up to 7 mAbs. Furthermore, the present method is the first to offer a simultaneous quantification of three immune checkpoint inhibitors likely to be associated in patients. Full article

(This article belongs to the Special Issue Precision Medicine in Oncology: Controlling the Pharmacokinetics Variability)

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15 pages, 1765 KiB

Open AccessArticle

Clinical-Based vs. Model-Based Adaptive Dosing Strategy: Retrospective Comparison in Real-World mRCC Patients Treated with Sunitinib

by Florent Ferrer, Jonathan Chauvin, Bénédicte DeVictor, Bruno Lacarelle, Jean-Laurent Deville and Joseph Ciccolini

Pharmaceuticals 2021, 14(6), 494; https://doi.org/10.3390/ph14060494 - 24 May 2021

Cited by 6 | Viewed by 3067

Abstract

Different target exposures with sunitinib have been proposed in metastatic renal cell carcinoma (mRCC) patients, such as trough concentrations or AUCs. However, most of the time, rather than therapeutic drug monitoring (TDM), clinical evidence is preferred to tailor dosing, i.e., by reducing the [...] Read more.

Different target exposures with sunitinib have been proposed in metastatic renal cell carcinoma (mRCC) patients, such as trough concentrations or AUCs. However, most of the time, rather than therapeutic drug monitoring (TDM), clinical evidence is preferred to tailor dosing, i.e., by reducing the dose when treatment-related toxicities show, or increasing dosing if no signs of efficacy are observed. Here, we compared such empirical dose adjustment of sunitinib in mRCC patients, with the parallel dosing proposals of a PK/PD model with TDM support. In 31 evaluable patients treated with sunitinib, 53.8% had an empirical change in dosing after treatment started (i.e., 46.2% decrease in dosing, 7.6% increase in dosing). Clinical benefit was observed in 54.1% patients, including 8.3% with complete response. Overall, 58.1% of patients experienced treatment discontinuation eventually, either because of toxicities or progressive disease. When choosing 50–100 ng/mL trough concentrations as a target exposure (i.e., sunitinib + active metabolite N-desethyl sunitinib), 45% patients were adequately exposed. When considering 1200–2150 ng/mL.h as a target AUC (i.e., sunitinib + active metabolite N-desethyl sunitinib), only 26% patients were in the desired therapeutic window. TDM with retrospective PK/PD modeling would have suggested decreasing sunitinib dosing in a much larger number of patients as compared with empirical dose adjustment. Indeed, when using target trough concentrations, the model proposed reducing dosing for 61% patients, and up to 84% patients based upon target AUC. Conversely, the model proposed increasing dosing in 9.7% of patients when using target trough concentrations and in 6.5% patients when using target AUC. Overall, TDM with adaptive dosing would have led to tailoring sunitinib dosing in a larger number of patients (i.e., 53.8% vs. 71–91%, depending on the chosen metrics for target exposure) than a clinical-based decision. Interestingly, sunitinib dosing was empirically reduced in 41% patients who displayed early-onset severe toxicities, whereas model-based recommendations would have immediately proposed to reduce dosing in more than 80% of those patients. This observation suggests that early treatment-related toxicities could have been partly avoided using prospective PK/PD modeling with adaptive dosing. Conversely, the possible impact of model-based adapted dosing on efficacy could not be fully evaluated because no clear relationship was found between baseline exposure levels and sunitinib efficacy measured at 3 months. Full article

(This article belongs to the Special Issue Precision Medicine in Oncology: Controlling the Pharmacokinetics Variability)

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11 pages, 1629 KiB

Open AccessArticle

Pharmacokinetics and Pharmacogenetics of Cyclophosphamide in a Neonate and Infant Childhood Cancer Patient Population

by Shelby Barnett, Julie Errington, Julieann Sludden, David Jamieson, Vianney Poinsignon, Angelo Paci and Gareth J. Veal

Pharmaceuticals 2021, 14(3), 272; https://doi.org/10.3390/ph14030272 - 16 Mar 2021

Cited by 13 | Viewed by 3692

Abstract

Infants and young children represent an important but much understudied childhood cancer patient population. The pharmacokinetics and pharmacogenetics of the widely used anticancer prodrug cyclophosphamide were investigated in children <2 years of age. Concentrations of cyclophosphamide and selected metabolites were determined in patients [...] Read more.

Infants and young children represent an important but much understudied childhood cancer patient population. The pharmacokinetics and pharmacogenetics of the widely used anticancer prodrug cyclophosphamide were investigated in children <2 years of age. Concentrations of cyclophosphamide and selected metabolites were determined in patients administered cyclophosphamide at doses ranging from 100–1500 mg/m² (5–75 mg/kg), with various infusion times as determined by the standard treatment regimen that each patient was receiving. Polymorphisms in genes including CYP2B6 and CYP2C19 were investigated. Data generated for cyclophosphamide were analysed using a previously published population pharmacokinetic model. Cyclophosphamide pharmacokinetics was assessed in 111 samples obtained from 25 patients ranging from 4–23 months of age. The average cyclophosphamide clearance for the patients was 46.6 mL/min/m² (ranging from 9.4–153 mL/min/m²), with marked inter-patient variability observed (CV 41%). No significant differences in cyclophosphamide clearance or exposure (AUC) were observed between patient groups as separated by age or body weight. However, marked differences in drug clearance and metabolism were noted between the current data in children <2 years of age and recently published results from a comparable study conducted by our group in older children, which reported significantly lower cyclophosphamide clearance values and metabolite exposures using the same population pharmacokinetic model for analysis. Whilst this study demonstrates no significant differences in cyclophosphamide clearance in patients <2 years, it highlights large differences in dosing protocols across tumour types. Furthermore, the study suggests marked differences in cyclophosphamide clearance in children less than two years of age as compared to older patients. Full article

(This article belongs to the Special Issue Precision Medicine in Oncology: Controlling the Pharmacokinetics Variability)

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14 pages, 1794 KiB

Open AccessArticle

Population Pharmacokinetics of Palbociclib in a Real-World Situation

by Bernard Royer, Courèche Kaderbhaï, Jean-David Fumet, Audrey Hennequin, Isabelle Desmoulins, Sylvain Ladoire, Siavoshe Ayati, Didier Mayeur, Sivia Ilie and Antonin Schmitt

Pharmaceuticals 2021, 14(3), 181; https://doi.org/10.3390/ph14030181 - 24 Feb 2021

Cited by 6 | Viewed by 2709

Abstract

Palbociclib is an oral cyclin-dependent kinase inhibitor that is used in combination with aromatase inhibitors in the treatment of postmenopausal women with metastatic breast cancer. Its metabolism profile is associated with an important interpatient variability. We performed a population pharmacokinetics study of palbociclib [...] Read more.

Palbociclib is an oral cyclin-dependent kinase inhibitor that is used in combination with aromatase inhibitors in the treatment of postmenopausal women with metastatic breast cancer. Its metabolism profile is associated with an important interpatient variability. We performed a population pharmacokinetics study of palbociclib in women routinely followed in a cancer center. One hundred and fifty-one samples were analyzed. The sampling times after administration ranged from 0.9 to 75 h and the samples were taken between 1 and 21 days after the beginning of the palbociclib cycle. Palbociclib was determined using a validated mass spectrometry method. The best model that described the concentrations was a one-compartment model with first-order absorption and an absorption lag time. Interindividual variability could only be estimated on the clearance and the first-order absorption. Creatinine clearance was found to be a significant covariate for the apparent clearance. No significant covariates could be observed with the first-order absorption. First-order absorption and absorption lag times were difficult to assess because of the constraints linked to the real-world setting due to the small number of samples used during the absorption process. However, palbociclib apparent clearance was satisfactorily estimated. Population pharmacokinetics (POP PK) with palbociclib could help to optimize dosing. Full article

(This article belongs to the Special Issue Precision Medicine in Oncology: Controlling the Pharmacokinetics Variability)

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13 pages, 1929 KiB

Open AccessArticle

Limited Sampling Strategy for Determination of Ibrutinib Plasma Exposure: Joint Analyses with Metabolite Data

by Félicien Le Louedec, Fanny Gallais, Fabienne Thomas, Mélanie White-Koning, Ben Allal, Caroline Protin, Loïc Ysebaert, Étienne Chatelut and Florent Puisset

Pharmaceuticals 2021, 14(2), 162; https://doi.org/10.3390/ph14020162 - 18 Feb 2021

Cited by 5 | Viewed by 3909

Abstract

Therapeutic drug monitoring of ibrutinib is based on the area under the curve of concentration vs. time (AUC_IBRU) instead of trough concentration (C_min,ss) because of a limited accumulation in plasma. Our objective was to identify a limited sampling strategy [...] Read more.

Therapeutic drug monitoring of ibrutinib is based on the area under the curve of concentration vs. time (AUC_IBRU) instead of trough concentration (C_min,ss) because of a limited accumulation in plasma. Our objective was to identify a limited sampling strategy (LSS) to estimate AUC_IBRU associated with Bayesian estimation. The actual AUC_IBRU of 85 patients was determined by the Bayesian analysis of the full pharmacokinetic profile of ibrutinib concentrations (pre-dose T0 and 0.5, 1, 2, 4 and 6 h post-dose) and experimental AUC_IBRU were derived considering combinations of one to four sampling times. The T0–1–2–4 design was the most accurate LSS (root-mean-square error RMSE = 11.0%), and three-point strategies removing the 1 h or 2 h points (RMSE = 22.7% and 14.5%, respectively) also showed good accuracy. The correlation between the actual AUC_IBRU and C_min,ss was poor (r² = 0.25). The joint analysis of dihydrodiol-ibrutinib metabolite concentrations did not improve the predictive performance of AUC_IBRU. These results were confirmed in a prospective validation cohort (n = 27 patients). At least three samples, within the pre-dose and 4 h post-dose period, are necessary to estimate ibrutinib exposure accurately. Full article

(This article belongs to the Special Issue Precision Medicine in Oncology: Controlling the Pharmacokinetics Variability)

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17 pages, 2631 KiB

Open AccessArticle

Design and Mechanism of Action of a New Prototype of Combi-Molecule “Programed” to Release Bioactive Species at a pH Range Akin to That of the Tumor Microenvironment

by Anne-Laure Larroque-Lombard, Etienne Chatelut, Jean-Pierre Delord, Diane-Charlotte Imbs, Philippe Rochaix, Bertrand Jean-Claude and Ben Allal

Pharmaceuticals 2021, 14(2), 160; https://doi.org/10.3390/ph14020160 - 16 Feb 2021

Cited by 3 | Viewed by 3926

Abstract

The clinical use of cytotoxic agents is plagued by systemic toxicity. We report a novel approach that seeks to design a “combi-molecule” to behave as an alkylating agent on its own and to undergo acid-catalyzed conversion to two bioactive species at a pH [...] Read more.

The clinical use of cytotoxic agents is plagued by systemic toxicity. We report a novel approach that seeks to design a “combi-molecule” to behave as an alkylating agent on its own and to undergo acid-catalyzed conversion to two bioactive species at a pH range akin to that of a tumor microenvironment: an AL530 prototype was synthesized and we studied its ability to release a chlorambucil analogue (CBL-A) plus a potent mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor (PD98059) at different pHs in buffered solutions, plasma and tumors. Its potency was compared in vitro with CBL+PD98059 (SRB assay) and in vivo in a xenograft model. Its target modulation was studied by western blotting and immunohistochemistry. AL530 released PD98059+CBL-A at mild acidic pH and in vitro was fivefold more potent than CBL and three-to-fivefold more potent than CBL+PD98059. In vivo it released high levels of PD98059 in tumors with a tumor/plasma ratio of five. It induced γ-H2AX phosphorylation and blocked pErk1,2, indirectly indicating its ability to damage DNA and modulate MEK. It induced significant tumor delay and less toxicity at unachievable doses for CBL and CBL+PD98059. We demonstrated the feasibility of a pH-labile combi-molecule capable of delivering high MEK inhibitor concentration in tumors, damaging DNA therein, and inducing tumor growth delay. Full article

(This article belongs to the Special Issue Precision Medicine in Oncology: Controlling the Pharmacokinetics Variability)

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10 pages, 1925 KiB

Open AccessArticle

Feasibility of Extrapolating Randomly Taken Plasma Samples to Trough Levels for Therapeutic Drug Monitoring Purposes of Small Molecule Kinase Inhibitors

by Ruben A. G. van Eerden, Esther Oomen-de Hoop, Aad Noordam, Ron H. J. Mathijssen and Stijn L. W. Koolen

Pharmaceuticals 2021, 14(2), 119; https://doi.org/10.3390/ph14020119 - 4 Feb 2021

Cited by 9 | Viewed by 2278

Abstract

Small molecule kinase inhibitors (SMKIs) are widely used in oncology. Therapeutic drug monitoring (TDM) for SMKIs could reduce underexposure or overexposure. However, logistical issues such as timing of blood withdrawals hamper its implementation into clinical practice. Extrapolating a random concentration to a trough [...] Read more.

Small molecule kinase inhibitors (SMKIs) are widely used in oncology. Therapeutic drug monitoring (TDM) for SMKIs could reduce underexposure or overexposure. However, logistical issues such as timing of blood withdrawals hamper its implementation into clinical practice. Extrapolating a random concentration to a trough concentration using the elimination half-life could be a simple and easy way to overcome this problem. In our study plasma concentrations observed during 24 h blood sampling were used for extrapolation to trough levels. The objective was to demonstrate that extrapolation of randomly taken blood samples will lead to equivalent estimated trough samples compared to measured C_min values. In total 2241 blood samples were analyzed. The estimated C_trough levels of afatinib and sunitinib fulfilled the equivalence criteria if the samples were drawn after T_max. The calculated C_trough levels of erlotinib, imatinib and sorafenib met the equivalence criteria if they were taken, respectively, 12 h, 3 h and 10 h after drug intake. For regorafenib extrapolation was not feasible. In conclusion, extrapolation of randomly taken drug concentrations to a trough concentration using the mean elimination half-life is feasible for multiple SMKIs. Therefore, this simple method could positively contribute to the implementation of TDM in oncology. Full article

(This article belongs to the Special Issue Precision Medicine in Oncology: Controlling the Pharmacokinetics Variability)

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11 pages, 1522 KiB

Open AccessArticle

Simulation-Based Assessment of the Impact of Non-Adherence on Endoxifen Target Attainment in Different Tamoxifen Dosing Strategies

by Anna Mueller-Schoell, Lena Klopp-Schulze, Robin Michelet, Madelé van Dyk, Thomas E. Mürdter, Matthias Schwab, Markus Joerger, Wilhelm Huisinga, Gerd Mikus and Charlotte Kloft

Pharmaceuticals 2021, 14(2), 115; https://doi.org/10.3390/ph14020115 - 3 Feb 2021

Cited by 4 | Viewed by 3198

Abstract

Tamoxifen is widely used in breast cancer treatment and minimum steady-state concentrations of its active metabolite endoxifen (C_{SS,min ENDX}) above 5.97 ng/mL have been associated with favourable disease outcome. Yet, about 20% of patients do not reach target C_{SS,min ENDX} [...] Read more.

Tamoxifen is widely used in breast cancer treatment and minimum steady-state concentrations of its active metabolite endoxifen (C_{SS,min ENDX}) above 5.97 ng/mL have been associated with favourable disease outcome. Yet, about 20% of patients do not reach target C_{SS,min ENDX} applying conventional tamoxifen dosing. Moreover, 4–75% of patients are non-adherent, resulting in worse disease outcomes. Assuming complete adherence, we previously showed model-informed precision dosing (MIPD) to be superior to conventional and CYP2D6-guided dosing in minimising the proportion of patients with subtarget C_{SS,min ENDX}. Given the high non-adherence rate in long-term tamoxifen therapy, this study investigated the impact of non-adherence on C_{SS,min ENDX} target attainment in different dosing strategies. We show that MIPD allows to account for the expected level of non-adherence (here: up to 2 missed doses/week): increasing the MIPD target threshold from 5.97 ng/mL to 9 ng/mL (the lowest reported C_{SS,min ENDX} in CYP2D6 normal metabolisers) as a safeguard resulted in the lowest interindividual variability and proportion of patients with subtarget C_{SS,min ENDX} even in non-adherent patients. This is a significant improvement to conventional and CYP2D6-guided dosing. Adding a fixed increment to the originally selected dose is not recommended, since it inflates interindividual variability. Full article

(This article belongs to the Special Issue Precision Medicine in Oncology: Controlling the Pharmacokinetics Variability)

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9 pages, 946 KiB

Open AccessArticle

The Influence of Body Composition on the Systemic Exposure of Paclitaxel in Esophageal Cancer Patients

by Leni van Doorn, Marie-Rose B. S. Crombag, Hánah N. Rier, Jeroen L. A. van Vugt, Charlotte van Kesteren, Sander Bins, Ron H. J. Mathijssen, Mark-David Levin and Stijn L. W. Koolen

Pharmaceuticals 2021, 14(1), 47; https://doi.org/10.3390/ph14010047 - 9 Jan 2021

Cited by 6 | Viewed by 2382

Abstract

Changes in body composition are associated with chemotherapy-related toxicities and effectiveness of treatment. It is hypothesized that the pharmacokinetics (PK) of chemotherapeutics may depend on body composition. The effects of body composition on the variability of paclitaxel PK were studied in patients with [...] Read more.

Changes in body composition are associated with chemotherapy-related toxicities and effectiveness of treatment. It is hypothesized that the pharmacokinetics (PK) of chemotherapeutics may depend on body composition. The effects of body composition on the variability of paclitaxel PK were studied in patients with esophageal cancer. Skeletal muscle index (SMI), visceral adipose tissue (VAT), and skeletal muscle density (SMD) were measured at the third lumbar vertebra on computed tomography (CT) scans performed before treatment. Paclitaxel PK data were collected from a prospective study performed between May 2004 and January 2014. Non-linear mixed-effects modeling was used to fit paclitaxel PK profiles and evaluate the covariates body surface area (BSA), SMI, VAT, and SMD using a significance threshold of p < 0.001. Paclitaxel was administered to 184 patients in a dose range of 50 to 175 mg/m². Median BSA was 1.98 m² (range of 1.4 to 2.8 m²). SMI, VAT, and SMD were not superior to BSA in predicting paclitaxel PK. The additive value of SMI, VAT, and SMD to BSA was also negligible. We did not find evidence that paclitaxel dosing could be further optimized by correcting for SMI, VAT, or SMD. Full article

(This article belongs to the Special Issue Precision Medicine in Oncology: Controlling the Pharmacokinetics Variability)

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11 pages, 789 KiB

Open AccessArticle

Association of 5-FU Therapeutic Drug Monitoring to DPD Phenotype Assessment May Reduce 5-FU Under-Exposure

by Marine Dolat, Pauline Macaire, Françoise Goirand, Julie Vincent, Audrey Hennequin, Rémi Palmier, Leïla Bengrine-Lefevre, François Ghiringhelli, Bernard Royer and Antonin Schmitt

Pharmaceuticals 2020, 13(11), 416; https://doi.org/10.3390/ph13110416 - 23 Nov 2020

Cited by 13 | Viewed by 3962

Abstract

In order to limit 5-fluorouracil (5-FU) toxicity, some health agencies recommend evaluating dihydropyrimidine dehydrogenase (DPD) deficiency before any 5-FU treatment introduction. In our study, we investigated relationships between 5-FU clearance and markers of DPD activity such as uracilemia (U), dihydrouracilemia (UH₂)/U [...] Read more.

In order to limit 5-fluorouracil (5-FU) toxicity, some health agencies recommend evaluating dihydropyrimidine dehydrogenase (DPD) deficiency before any 5-FU treatment introduction. In our study, we investigated relationships between 5-FU clearance and markers of DPD activity such as uracilemia (U), dihydrouracilemia (UH₂)/U ratio, or genotype of the gene encoding DPD (DPYD). All patients with gastrointestinal cancers who received 5-FU-based regimens form March 2018 to June 2020 were included in our study. They routinely benefited of a pre-therapeutic DPYD genotyping and phenotyping. During 5-FU infusion, blood samples were collected to measure 5-FU steady-state concentration in order to adapt 5-FU doses at the following cycles. A total of 169 patients were included. Median age was 68 (40–88) years and main primary tumor sites were colorectal (40.8%) and pancreas (31.4%), metastatic in 76.3%. 5-FU was given as part of FOLFIRINOX (44.4%), simplified FOLFOX-6 (26.6%), or docetaxel/FOLFOX-4 (10.6%). Regarding DPD activity, median U and UH₂/U were, respectively, 10.8 ng/mL and 10.1, and almost 15% harbored a heterozygous mutation. On the range of measured U and UH₂/U, no correlation was observed with 5-FU clearance. Moreover, in patients with U < 16 ng/mL, 5-FU exposure was higher than in other patients, and most of them benefited of dose increase following 5-FU therapeutic drug monitoring (TDM). If recent guidelines recommend decreasing 5-FU dose in patients harboring U ≥ 16 ng/mL, our study highlights that those patients are at risk of under-exposure and that 5-FU TDM should be conducted in order to avoid loss of efficacy. Full article

(This article belongs to the Special Issue Precision Medicine in Oncology: Controlling the Pharmacokinetics Variability)

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12 pages, 899 KiB

Open AccessFeature PaperArticle

by Jocelyn Gal, Gérard Milano, Patrick Brest, Nathalie Ebran, Julia Gilhodes, Laurence Llorca, Coraline Dubot, Gilles Romieu, Isabelle Desmoulins, Etienne Brain, Anthony Goncalves, Jean-Marc Ferrero, Paul-Henri Cottu, Marc Debled, Olivier Tredan, Emmanuel Chamorey, Marco Carlo Merlano, Jérôme Lemonnier, Marie-Christine Etienne-Grimaldi and Jean-Yves Pierga

Pharmaceuticals 2020, 13(11), 414; https://doi.org/10.3390/ph13110414 - 23 Nov 2020

Cited by 6 | Viewed by 2695

Abstract

The prospective multicenter COMET trial followed a cohort of 306 consecutive metastatic breast cancer patients receiving bevacizumab and paclitaxel as first-line chemotherapy. This study was intended to identify and validate reliable biomarkers to better predict bevacizumab treatment outcomes and allow for a more [...] Read more.

The prospective multicenter COMET trial followed a cohort of 306 consecutive metastatic breast cancer patients receiving bevacizumab and paclitaxel as first-line chemotherapy. This study was intended to identify and validate reliable biomarkers to better predict bevacizumab treatment outcomes and allow for a more personalized use of this antiangiogenic agent. To that end, we aimed to establish risk scores for survival prognosis dichotomization based on classic clinico-pathological criteria combined or not with single nucleotide polymorphisms (SNPs). The genomic DNA of 306 patients was extracted and a panel of 13 SNPs, covering seven genes previously documented to be potentially involved in drug response, were analyzed by means of high-throughput genotyping. In receiver operating characteristic (ROC) analyses, the hazard model based on a triple-negative cancer phenotype variable, combined with specific SNPs in VEGFA (rs833061), VEGFR1 (rs9582036) and VEGFR2 (rs1870377), had the highest predictive value. The overall survival hazard ratio of patients assigned to the poor prognosis group based on this model was 3.21 (95% CI (2.33–4.42); p < 0.001). We propose that combining this pharmacogenetic approach with classical clinico-pathological characteristics could markedly improve clinical decision-making for breast cancer patients receiving bevacizumab-based therapy. Full article

(This article belongs to the Special Issue Precision Medicine in Oncology: Controlling the Pharmacokinetics Variability)

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10 pages, 1495 KiB

Open AccessCase Report

Combining Sorafenib and Immunosuppression in Liver Transplant Recipients with Hepatocellular Carcinoma

by Koen G. A. M. Hussaarts, Leni van Doorn, Sander Bins, Dave Sprengers, Peter de Bruijn, Roelof W. F. van Leeuwen, Stijn L. W. Koolen, Teun van Gelder and Ron H. J. Mathijssen

Pharmaceuticals 2021, 14(1), 46; https://doi.org/10.3390/ph14010046 - 9 Jan 2021

Cited by 8 | Viewed by 3087

Abstract

Hepatocellular carcinoma (HCC) recurrence after liver transplantation occurs in approximately 20% of patients. Most of these patients use immunosuppressant drugs. Meanwhile, patients with HCC recurrence are frequently treated with the small molecule kinase inhibitor (SMKI) sorafenib. However, sorafenib and many immunosuppressants are substrates [...] Read more.

Hepatocellular carcinoma (HCC) recurrence after liver transplantation occurs in approximately 20% of patients. Most of these patients use immunosuppressant drugs. Meanwhile, patients with HCC recurrence are frequently treated with the small molecule kinase inhibitor (SMKI) sorafenib. However, sorafenib and many immunosuppressants are substrates of the same enzymatic pathways (e.g., CYP3A4), which may potentially result in altered SMKI or immunosuppressant plasma levels. Therefore, we investigated changes in drug exposure of both sorafenib and immunosuppressants over time in four patients with systemic immunosuppressant and sorafenib treatment after HCC recurrence. In this study, sorafenib exposure declined over time during combined treatment with immunosuppressants, while two patients also experienced declining tacrolimus plasma levels. Importantly, patients were unable to increase the sorafenib dose higher than 200 mg b.i.d. without experiencing significant toxicity. We recommend to treat patients using both sorafenib and immunosuppressants with a sorafenib starting dose of 200 mg b.i.d. Full article

(This article belongs to the Special Issue Precision Medicine in Oncology: Controlling the Pharmacokinetics Variability)

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