Population pharmacokinetics of FOLFIRINOX: a review of studies and parameters

Deyme, Laure; Barbolosi, Dominique; Gattacceca, Florence

doi:10.1007/s00280-018-3722-5

Cited by 24 publications

(34 citation statements)

References 39 publications

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“…The current investigations are of particular value because they establish a link between 5FU PK and myelosuppression in the same patients, where we were also able to characterize the PD interaction between 5FU and cisplatin. Approaches adapted to describe pharmacokinetics of 5FU have been nicely summarized by Deyme et al [14]. In most of the cases, a two-compartment model was found adequate to describe 5FU PK [3,[37][38][39], while some studies presented a one-compartment model [6,40].…”

Section: Discussionmentioning

confidence: 99%

“…Another simulation scenario aimed towards the comparative assessment of the time course of myelosuppression theoretically produced by the 5FU component contained in a single cycle of the two standard dosage regimens used in current clinical practice; to this end, the effects of the other components of the regimens were ignored. The standard FOLFIRINOX regimen combines oxaliplatin (85 mg/ m 2 over 2 h) with folinic acid (200 mg/m 2 ) followed by irinotecan (180 mg/m 2 over 90 min) and 5FU (400 mg/m 2 bolus) followed by 2400 mg/m 2 5FU over 46 h, all on day 1 and repeated every 2 weeks [14]. The de Gramont regimen is described as follows: high-dose folinic acid (200 mg/ m 2 ) followed by 5FU i.v.…”

Section: Simulation Designmentioning

confidence: 99%

“…5FU is commonly used in combination with other antineoplastic drugs and with radiotherapy. A therapeutic regimen known as FOLFIRINOX including 5FU, folinic acid, oxaliplatin and irinotecan is frequently employed for the treatment of colorectal and pancreatic cancer [14]. Another regimen, called de Gramont, includes a combination of 5FU and leucovorin (folinic acid) and has been reported to possess low-toxicity profile, increased response rate and progression-free survival [15].…”

Section: Introductionmentioning

confidence: 99%

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Prediction of exposure-driven myelotoxicity of continuous infusion 5-fluorouracil by a semi-physiological pharmacokinetic–pharmacodynamic model in gastrointestinal cancer patients

Arshad

Ploylearmsaeng

Karlsson

et al. 2020

Cancer Chemother Pharmacol

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Purpose To describe 5-fluorouracil (5FU) pharmacokinetics, myelotoxicity and respective covariates using a simultaneous nonlinear mixed effect modelling approach. Methods Thirty patients with gastrointestinal cancer received 5FU 650 or 1000 mg/m 2 /day as 5-day continuous venous infusion (14 of whom also received cisplatin 20 mg/m 2 /day). 5FU and 5-fluoro-5,6-dihydrouracil (5FUH2) plasma concentrations were described by a pharmacokinetic model using NONMEM. Absolute leukocyte counts were described by a semimechanistic myelosuppression model. Covariate relationships were evaluated to explain the possible sources of variability in 5FU pharmacokinetics and pharmacodynamics. Results Total clearance of 5FU correlated with body surface area (BSA). Population estimate for total clearance was 249 L/h. Clearances of 5FU and 5FUH2 fractionally changed by 77%/m 2 difference from the median BSA. 5FU central and peripheral volumes of distribution were 5.56 L and 28.5 L, respectively. Estimated 5FUH2 clearance and volume of distribution were 121 L/h and 96.7 L, respectively. Baseline leukocyte count of 6.86 × 10 9 /L, as well as mean leukocyte transit time of 281 h accounting for time delay between proliferating and circulating cells, was estimated. The relationship between 5FU plasma concentrations and absolute leukocyte count was found to be linear. A higher degree of myelosuppression was attributed to combination therapy (slope = 2.82 L/mg) with cisplatin as compared to 5FU monotherapy (slope = 1.17 L/mg). Conclusions BSA should be taken into account for predicting 5FU exposure. Myelosuppression was influenced by 5FU exposure and concomitant administration of cisplatin.

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Section: Discussionmentioning

confidence: 99%

Section: Simulation Designmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prediction of exposure-driven myelotoxicity of continuous infusion 5-fluorouracil by a semi-physiological pharmacokinetic–pharmacodynamic model in gastrointestinal cancer patients

Arshad

Ploylearmsaeng

Karlsson

et al. 2020

Cancer Chemother Pharmacol

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“…Next, important intra-patient variabilities arise from the 29 fact that tumour and healthy tissues, rather than being static over time, display 30 time-dependent variations, in particular over the 24h span, which are called circadian 31 rhythms [11]. The circadian timing system controls most physiological functions of the 32 organism resulting in drug Absorption, Distribution, Metabolism and Elimination 33 (ADME) displaying 24h-rhythms with differences of up to several folds between 34 minimum and maximum activities [12,13]. 35 Chronotherapy -that is administering drugs according to the patient's biological 36 rhythms over 24 h-is a growing field in medicine and especially in oncology.…”

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confidence: 99%

“…However, the data available in the OPTILIV study would not 326 allow for estimating parameters of such a detailed model. Next, numerous clinical 327 studies have performed compartment analysis of plasma PK data from cancer patients 328 receiving either 5-fluorouracil, oxaliplatin or irinotecan [33]. These models were 329 designed for intravenous injection and could not be readily used for intra-arterial 330 hepatic administration.…”

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confidence: 99%

Optimizing drug infusion schedules towards personalized cancer chronotherapy

Hill

Innominato

Lévi

et al. 2019

Preprint

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AimsPrecision medicine requires accurate technologies for drug administration and proper systems pharmacology approaches for patient data analysis. Here, plasma pharmacokinetics (PK) data of the OPTILIV trial in which cancer patients received oxaliplatin, 5-fluorouracil and irinotecan via chronomodulated schedules delivered by an infusion pump into the hepatic artery were mathematically investigated. MethodsA pump-to-patient model was designed in order to accurately represent the drug solution dynamics from the pump to the patient blood. It was connected to semi-mechanistic PK models to analyse inter-patient variability in PK parameters. ResultsLarge time delays of up to 1h41 between the actual pump start and the time of drug detection in patient blood was predicted by the model and confirmed by PK data. Sudden delivery spike in the patient artery due to glucose rinse after drug administration accounted for up to 10.7% of the total drug dose. New model-guided delivery profiles were designed to precisely lead to the drug exposure intended by clinicians. Next, the complete mathematical framework achieved a very good fit to individual time-concentration PK profiles and concluded that inter-subject differences in PK parameters was the lowest for irinotecan, intermediate for oxaliplatin and the largest for 5-fluorouracil. Clustering patients according to their PK parameter values revealed two patient subgroups for each drug in which inter-patient variability was largely decreased compared to that in the total population. ConclusionsThis study provides a complete mathematical framework to optimize drug infusion pumps and inform on inter-patient PK variability, a step towards precise and personalized cancer chronotherapy. Author summaryAccuracy and safety of infusion pumps remain a critical issue in the clinics and the development of accurate mathematical models to optimize drug administration though such devices has a key part to play in the advancement of precision medicine. Here, PK data from cancer patient receiving irinotecan, oxaliplatin and 5-fluorouracil into the hepatic artery via an infusion pump was mathematically investigated. A pump-to-patient model was designed and revealed significant inconsistencies between intended drug profiles and actual plasma concentrations. This mathematical model was then used to suggest improved profiles in order to minimise error and optimise delivery. Physiologically-based PK models of the three drugs were then linked to the pump-to-patient model. The whole framework achieved a very good fit to data and allowed quantifying inter-patient variability in PK parameters and linking them to potential clinical biomarkers via patient clustering. The developed methodology improves our understanding of patient-specific drug pharmacokinetics towards personalized drug administration.

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Efficacy and safety of chronomodulated irinotecan, oxaliplatin, 5‐fluorouracil and leucovorin combination as first‐ or second‐line treatment against metastatic colorectal cancer: Results from the International EORTC 05011 Trial

Innominato

Karaboué

Focan

et al. 2020

Intl Journal of Cancer

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The triplet combination of irinotecan, oxaliplatin and fluorouracil is an active frontline regimen in metastatic colorectal cancer, but scarce data exist on its use as salvage treatment. We aimed at assessing its safety and efficacy profiles with its circadian‐based administration (chronoIFLO5) as either first‐ or second‐line treatment, within the time‐finding EORTC 05011 trial. Five‐day chronoIFLO5 was administered every 3 weeks in patients with PS 0, 1 or 2. It consisted of chronomodulated irinotecan (180 mg/sqm), oxaliplatin (80 mg/sqm) and fluorouracil‐leucovorin (2800 and 1200 mg/sqm, respectively). For our study, toxicity and antitumour activity were evaluated separately in first‐ and second‐line settings. Primary endpoints included Grade 3‐4 toxicity rates, best objective response rate (ORR), progression‐free survival (PFS) and overall survival (OS). One‐hundred forty‐nine and 44 patients were treated in first‐line and second‐line settings, respectively, with a total of 1138 cycles with median relative dose intensities of about 90%. Demographics were comparable in the two groups. Thirty‐six (24.7%) and 10 (22.2%) patients experienced at least one episode of severe toxicity in first line and second line, respectively. Frontline chronoIFLO5 yielded an ORR of 62.3% [95% CI: 54.2‐70.4] and resulted in median PFS and OS of 8.7 months [7.5‐9.9] and 19.9 months [15.4‐24.5]. Corresponding figures in second line were 37.5% [22.5‐52.5], 6.7 months [4.8‐8.9] and 16.3 months [11.8‐20.8]. International and prospective evaluation revealed the favourable safety and efficacy profiles of chronoIFLO5, both as frontline and as salvage treatment against metastatic colorectal cancer. In particular, encouraging activity in second line was observed, with limited haematological toxicity.

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Population pharmacokinetics of FOLFIRINOX: a review of studies and parameters

Cited by 24 publications

References 39 publications

Prediction of exposure-driven myelotoxicity of continuous infusion 5-fluorouracil by a semi-physiological pharmacokinetic–pharmacodynamic model in gastrointestinal cancer patients

Prediction of exposure-driven myelotoxicity of continuous infusion 5-fluorouracil by a semi-physiological pharmacokinetic–pharmacodynamic model in gastrointestinal cancer patients

Optimizing drug infusion schedules towards personalized cancer chronotherapy

Efficacy and safety of chronomodulated irinotecan, oxaliplatin, 5‐fluorouracil and leucovorin combination as first‐ or second‐line treatment against metastatic colorectal cancer: Results from the International EORTC 05011 Trial

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