Genetic relationships between efficiency traits and gut microbiota traits in growing pigs being fed with a conventional or a high-fiber diet.

In pigs, the gut microbiota composition plays a major role in the process of digestion, but is influenced by many external factors, especially diet. To be used in breeding applications, genotype by diet interactions on microbiota composition have to be quantified, as well as their impact on genetic covariances with feed efficiency (FE) and digestive efficiency (DE) traits. This study aimed at determining the impact of an alternative diet on variance components of microbiota traits (genera and alpha diversity indices) and estimating genetic correlations between microbiota and efficiency traits for pigs fed a conventional (CO) or a high-fiber (HF) diet. Fecal microbes of 812 full-siblings fed a CO diet and 752 pigs fed the HF diet were characterized at 16 weeks of age by sequencing the V3-V4 region of the 16S rRNA gene. A total of 231 genera were identified. Digestibility coefficients of nitrogen, organic matter, and energy were predicted analyzing the same fecal samples with near infrared spectrometry. Daily feed intake, feed conversion ratio, residual feed intake and average daily gain (ADG) were also recorded. The 71 genera present in more than 20% of individuals were retained for genetic analyses. Heritability (h²) of microbiota traits were similar between diets (from null to 0.38 ±â€…0.12 in the CO diet and to 0.39 ±â€…0.12 in the HF diet). Only three out of the 24 genera and two alpha diversity indices with significant h² in both diets had genetic correlations across diets significantly different from 0.99 (P < 0.05), indicating limited genetic by diet interactions for these traits. When both diets were analyzed jointly, 59 genera had h² significantly different from zero. Based on the genetic correlations between these genera and ADG, FE, and DE traits, three groups of genera could be identified. A group of 29 genera had abundances favorably correlated with DE and FE traits, 14 genera were unfavorably correlated with DE traits, and the last group of 16 genera had abundances with correlations close to zero with production traits. However, genera abundances favorably correlated with DE and FE traits were unfavorably correlated with ADG, and vice versa. Alpha diversity indices had correlation patterns similar to the first group. In the end, genetic by diet interactions on gut microbiota composition of growing pigs were limited in this study. Based on this study, microbiota-based traits could be used as proxies to improve FE and DE in growing pigs.

The link between the composition of the gut microbiota, i.e the composition of microorganisms in the gut, in pigs and their feed efficiency, i.e. their ability to utilize nutrients, as well as their ability to digest were studied from a genetic point of view. A family structure of 1,564 pigs were studied and fed with two different diets. One of the full-sib was fed a conventional diet used in breeding farms and the other one an alternative diet containing raw materials, less expensive but with a higher content of dietary fibers more difficult to digest. This study has shown that some microbiota microorganisms were genetically correlated with feed and digestive efficiency performances, positively or negatively, depending on the microorganisms. In addition, the diversity of microorganisms in the animal's gut was favorably correlated with the feed and digestive performances studied. Therefore, there is a genetic link between these performances and the composition of the animal's gut microbiota. Thus, a potential genetic selection on some intestinal microorganisms or diversity of microorganisms would allow to improve these performances, and in particular when pigs are fed with diet more difficult to digest.

Digestive efficiency traits in growing pigs are genetically correlated with sow litter traits in the Large White breed.

Digestive efficiency traits are promising selection criteria to improve feed efficiency in pigs. However, the genetic relationships between digestive efficiency and sow reproductive traits are mostly unknown and need to be estimated. In this study, reproductive traits were available for 61 601 litters recorded on 21 719 Large White purebred sows. The traits were comprised of the number of born alive (NBA) and the number of weaned piglets (NWP), the number of stillbirths (NSB) and piglet mortality during suckling (PM). For a subset of 32518 litters, the mean (MBW) and CV of piglet birth weights (CVBW) were deduced from individual piglet weights as well as the proportion of piglets weighing less than 1 kg (PPL1K). Growth and feed efficiency traits were available for 4 643 Large White male pigs related to sows with reproductive performances. They comprised average daily gain (ADG), daily feed intake (DFI) and feed conversion ratio (FCR). A subset of 1 391 pigs had predictions for digestibility coefficients (DC) of energy, organic matter and nitrogen obtained by analysing faecal samples with near-infrared spectrometry. Estimated heritabilities were low for NBA, NSB, NWP and PM (0.08 ± 0.01 to 0.11 ± 0.01) and low to moderate for litter weight characteristics (0.14 ± 0.02 to 0.38 ± 0.01). Heritability estimates were moderate to high for ADG, DFI and FCR (0.37 ± 0.04 to 0.54 ± 0.05) and moderate for DC traits (0.26 ± 0.06 to 0.38 ± 0.07). Genetic correlations were low between ADG, or alternatively FCR, and reproductive traits. They were significantly different from zero with MBW (0.19 ± 0.06 with ADG and -0.15 ± 0.06 with FCR) and PPL1K (-0.19 ± 0.07 with ADG and 0.18 ± 0.07 with FCR). All genetic correlations between DFI and reproductive traits were low and not significantly different from zero. Genetic correlations between DC traits and NBA were significantly different from zero for DC of organic matter and energy (<-0.25 ± 0.11). DC traits were moderately correlated with MBW (>0.30 ± 0.11), CVBW (<-0.36 ± 0.11) and PPL1K (<-0.37 ± 0.11) at the genetic level. Genetic correlations between DC traits and PM were significantly negative and hence favourable (<-0.38 ± 0.12). Finally, genetic correlations between DC traits and NWP were close to zero. These results suggested that sows closely related to growing pigs with the best digestive efficiency would produce heavier and more homogeneous piglets, with slightly smaller litter sizes at birth but better survival. Hence, there is usable genetic variation in DC that could be exploited to define new selection strategies in maternal lines aiming at improving not only feed efficiency but also piglet survival.

Association of cabozantinib pharmacokinetics, progression and toxicity in metastatic renal cell carcinoma patients: results from a pharmacokinetics/pharmacodynamics study.

BACKGROUND: Cabozantinib is a tyrosine kinase inhibitor with a substantial efficacy in metastatic renal cell carcinoma, and is associated with a challenging toxicity profile leading to frequent drug discontinuations. Whereas an exposure/safety relationship was demonstrated for this drug, an exposure/efficacy relationship is still unknown. PATIENTS AND METHODS: We carried out a monocentric, observational, pharmacokinetics/pharmacodynamics (PK/PD) study in patients with metastatic renal cell carcinoma (INDS MR 5612140520). We used measured blood concentrations of cabozantinib (Cmeas) to determine the area under the curve (AUC), apparent clearance (Cl/F) and residual blood concentration (Ctrough). Best overall response according to RECIST 1.1 and relevant toxicity (adverse event grade 3-4 or grade 2 requiring dose reduction or discontinuation) were assessed according to Cmeas, Ctrough, AUC and Cl/F. RESULTS: We enrolled 76 patients, including 35 who experienced disease progression and 30 with grade 3-4 toxicity. Patients with progressive disease had a significantly lower median Ctrough (406 versus 634 ng/ml, P = 0.001), Cl/F (2 versus 2.9 l/h, P = 0.002) and AUC (16 versus 20 µg h/ml, P = 0.037) compared with patients who had disease control as best response. Patients with relevant toxicity had a significantly higher Cmeas (732 versus 531 ng/ml, P = 0.006), Ctrough (693 versus 521 ng/ml, P = 0.005) and AUC (21 versus 16 µg h/ml, P = 0.046) compared with patients who did not experience any grade relevant toxicity. Receiver operating characteristic curves obtained from our study defined a threshold for drug efficacy of 536.8 ng/ml and of 617.7 ng/ml for toxicity. CONCLUSION: We first demonstrate the PK/PD relationship for cabozantinib. Severe toxicities are associated with a higher drug exposure, whereas inefficacy is associated with a lower drug exposure. Cabozantinib plasma drug monitoring may be useful to optimize clinical practice.

Impact of a high-fibre diet on genetic parameters of production traits in growing pigs.

The use of diets with increased fibre content from alternative feedstuffs less digestible for pigs is a solution considered to limit the impact of increased feed costs on pig production. This study aimed at determining the impact of an alternative diet on genetic parameters for growth, feed efficiency, carcass composition and meat quality traits. A total of 783 Large White pigs were fed a high-fibre (HF) diet and 880 of their sibs were fed a conventional (CO) cereal-based diet. Individual daily feed intake, average daily gain, feed conversion ratio and residual feed intake were recorded as well as lean meat percentage (LMP), carcass yield (CY) and meat quality traits. Pigs fed the CO diet had better performances for growth and feed efficiency than pigs fed the HF diet. They also had lower LMP and higher CY. In addition, pigs fed the CO diet had lower loin percentage and ham percentage and higher backfat percentage. No differences were observed in meat quality traits between diets, except for a* and b* values. For all traits, the genetic variances and heritability were not different between diets. Genetic correlations for traits between diets ranged between 0.80 ± 0.13 and 0.99 ± not estimable, and none were significantly different from 0.99, except for LMP. Thus, traits in both diets were considered as mainly affected by similar sets of genes in the two diets. A genetic correlation lower than 0.80 would justify redesigning the breeding scheme; however, some genetic correlations did not differ significantly from 0.80 either. Therefore, larger populations are needed for a more definitive answer regarding the design of the breeding scheme. To further evaluate selection strategies, a production index was computed within diets for the 29 sires with estimated breeding value reliability higher than 0.35. The rank correlation between indices estimated in the CO and in the HF diet was 0.72. Altogether, we concluded that limited interaction between feed and genetics could be evidenced, and based on these results there is no need to change pig selection schemes to adapt to the future increased use of alternative feedstuffs in production farms.

Genetic determinism of boar taint and relationship with growth traits, meat quality and lesions.

Breeding entire males is an alternative to surgical castration to improve their welfare. However, entire males may have a major quality defect called boar taint. Boar taint is partly due to the presence of androstenone in fat. In this study, we estimated the genetic parameters between androstenone and production traits to evaluate the consequences of selection against boar taint for traits of interest. We focused on growth traits, meat quality, lesions, hormone levels and computerised tomography measurements in purebred Piétrain (P) or Piétrain cross Large White (X) entire males. The number of measured animals varied from 670 P and 734 X for hormones concentrations to 553 P and 645 X for computerised tomography measurements. Skin lesions were measured on live pigs shortly after mixing, at the end of the fattening period, and on carcasses. Heritabilities of traits measured by tomography ranged from low to high: femur density (P: 0.34, X: 0.69), loin eye area (P: 0.53, X: 0.88) and loin eye density (P: 0.12, X: 0.18). The mean number of lesions at each stage was lower in purebred pigs than in crossbreds (entering the fattening stage 4.01 in P and 4.68 in X; before slaughter 3.72 in P and 4.22 in X; on carcass 4.50 in P and 4.96 in X). We also observed a decrease in the average number of lesions between the two stages in live pigs. We found high genetic correlations between stages in purebred pigs (0.74 to 0.76) but low correlations (-0.30 to 0.29) in crossbred pigs. Selection aiming to decrease fat androstenone is feasible (h2 = 0.57 in P and h2 = 0.71 in X). It would have overall positive effects on meat production and quality traits. Selection aiming to reduce plasma oestradiol would strongly reduce the level of fat androstenone (rg = 0.89 in P and rg = 0.84 in X). Selection against oestradiol is easier and less invasive since it would only require a blood sample rather than a fat biopsy in live animals.

Determinants of the interindividual variability in serum cytidine deaminase activity of patients with solid tumours.

AIMS: Cytidine deaminase (CDA) activity in cancer patients' serum has been proposed as a predictive biomarker for efficacy and toxicity of nucleoside analogues. However, discrepant results about its predictive value have been reported due to the high interindividual variability in CDA activity. This study aimed at identifying determinants of this interindividual variability. METHODS: From December 2014 to November 2015, 183 patients were prospectively included. Serum CDA activity, biological and clinical characteristics as well as five common single nucleotide polymorphisms (SNPs) in the CDA gene (c.-451C > T, c.-92A > G, c.-33_-31delC, c.79A > C, c.435 T > C) were analysed. Associations between clinical characteristics, pharmacogenetic variants and CDA activity were univariately tested. P < 0.1-candidate variables were analysed through a multivariate analysis. The association between CDA activity and toxicity was assessed for the 56 gemcitabine-treated patients. Intraindividual variability in CDA activity was explored in six pancreatic cancer patients treated with gemcitabine. RESULTS: Median CDA activity was 3.97 U mg-1 (range 1.53-15.49 U mg-1 ). A univariate analysis showed that CDA activity was statistically associated with Eastern Cooperative Oncology Group performance status, mild or severe malnutrition, inflammatory syndrome, leucocyte count, neutrophil count, albumin, C-reactive protein and -c.-33_-31delC single nucleotide polymorphism. A multivariate analysis identified that only neutrophil count (P < 0.0001) and severe malnutrition (P = 0.0278) were independently associated with CDA activity. Low CDA activity (<2 U mg-1 ) was not statistically associated with severe gemcitabine-related toxicities (P = 0.16). A decrease in CDA activity was observed during the longitudinal follow-up of six pancreatic cancer patients treated with gemcitabine (P = 0.03). CONCLUSIONS: These results suggest that neutrophil count and malnutrition should be considered for the interpretation of pretherapeutic CDA activity.

Relation between plasma trough concentration of abiraterone and prostate-specific antigen response in metastatic castration-resistant prostate cancer patients.

BACKGROUND: Abiraterone (ABI) is a major oral agent for the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients but its systemic exposure is subject to a large inter-individual variability. We aimed to explore the relationship between ABI trough plasma concentration and prostate-specific antigen (PSA) response in mCRPC patients and to identify the critical determinants for its activity. PATIENTS AND METHODS: This is a monocentric prospective observational study in mCRPC patients treated with ABI. The plasmatic concentration of ABI at steady state was measured using liquid chromatography with fluorescence detection. The primary objective was to study the relationship between mean ABI plasma exposure (ABI Cmin) and 3-month PSA response. RESULTS: From 2012 to 2016, 61 mCRPC patients were eligible for pharmacokinetic/pharmacodynamic assessment. Thirty-eight patients experienced PSA response (62%, [confidence interval {CI} 95% 50-78]). In univariate analysis, ABI Cmin was 1.5-fold higher in responders: 12.0 ng/mL (CI 95% 9.4-15.6) versus 8.0 ng/mL (CI 95% 5.8-11.6; P = 0.0015). In multivariate analysis, only ABI Cmin was independently associated with PSA response (odds ratio = 1.12 [CI 95% 1.01-1.25], P = 0.004). By receiver operating characteristic analysis, the optimal threshold for ABI Cmin was 8.4 ng/mL. Progression-free survival (PFS) was significantly higher in patients with ABI Cmin above 8.4 ng/mL (hazard ratio 0.55, [CI 95% 0.31-0.99], 12.2 [CI 95% 9.2-19.5] versus 7.4 [CI 95% 5.5-14.7] months otherwise, P = 0.044). CONCLUSIONS: We showed that ABI trough concentration correlates with PSA response and PFS. Moreover, we could determine a cut-off value of plasmatic concentration for PSA response. Altogether, ABI concentration monitoring appears as a new approach to improve clinical outcome in mCPRC patients.

Vemurafenib pharmacokinetics and its correlation with efficacy and safety in outpatients with advanced BRAF-mutated melanoma.

Vemurafenib is a BRAF kinase inhibitor approved for first-line treatment of metastatic BRAF (V600) -mutant melanoma. However, data on the pharmacokinetic/pharmacodynamic (PK/PD) relationship are lacking. The aim of this prospective, multicenter study was to explore the PK/PD relationship for vemurafenib in outpatients with advanced BRAF-mutated melanoma. Fifty-nine patients treated with single-agent vemurafenib were prospectively analyzed. Vemurafenib plasma concentration (n = 159) was measured at days 15, 30, 60, and 90 after treatment initiation. Clinical and biological determinants (including plasma vemurafenib concentration) for efficacy and safety were assessed using Cox's model and multivariate stepwise logistic regression. Median progression-free survival (PFS) and overall survival were 5.0 (95 % confidence interval [95 % CI] 2.0-6.0) and 11.0 (95% CI 7.0-16.0) months, respectively. Twenty-nine patients (49 %) experienced any grade ≥3 toxicity and the most frequent grade ≥2 toxicity was skin rash (37 %). Severe toxicities led to definitive discontinuation in seven patients (12 %). Grade ≥2 skin rash was not statistically associated with better objective response at day 60 (p = 0.06) and longer PFS (hazard ratio 0.47; 95 % CI 0.21-1.08; p = 0.075). Grade ≥2 skin rash was statistically increased in patients with ECOG ≥ 1 (odds ratio 4.67; 95 % CI 1.39-15.70; p = 0.012). Vemurafenib concentration below 40.4 mg/L at day 15 was significantly associated with a shorter PFS (1.5 [0.5-5.5] vs. 4.5 [2-undetermined] months, p = 0.029). Finally, vemurafenib concentration was significantly greater in patients developing grade ≥2 rash (61.7 ± 25.0 vs. 36.3 ± 17.9 mg/L, p < 0.0001). These results suggest that early plasma drug monitoring may help identify outpatients at high risk of non-response or grade ≥ 2 skin rash.

Determinants of hydroxychloroquine blood concentration variations in systemic lupus erythematosus.

OBJECTIVE: Blood concentrations of hydroxychloroquine (HCQ) vary widely among patients with systemic lupus erythematosus (SLE). A pharmacokinetic/pharmacodynamic relationship has been found in different situations, and a very low blood concentration of HCQ is a simple marker of nonadherence to treatment. Therefore, interest in blood HCQ concentration measurement has increased, but little is known about factors that influence blood HCQ concentration variability. This study was undertaken to analyze determinants of blood HCQ concentrations. METHODS: We conducted a retrospective analysis of patient data, including data from the Plaquenil Lupus Systemic (PLUS) study, to determine the association of epidemiologic, clinical, and biologic factors with blood HCQ concentrations. Data for nonadherent patients (blood HCQ concentration <200 ng/ml) were excluded. RESULTS: To examine homogeneous pharmacologic data, we restricted the analyses of the PLUS data to the 509 SLE patients receiving 400 mg/day. We found no association of ethnicity or smoking with blood HCQ concentrations and no pharmacokinetic drug-drug interaction with antacids or with inhibitors or inducers of cytochrome P450 enzymes. On multivariate analysis, high body mass index (P = 0.008), no treatment with corticosteroids (P = 0.04), increased time between the last tablet intake and measurement of blood HCQ concentrations (P = 0.017), low platelet count (P < 0.001), low neutrophil count (P < 0.001), and high estimated creatinine clearance (P < 0.001) were associated with low blood HCQ concentrations. In 22 SLE patients with chronic renal insufficiency (median serum creatinine clearance 52 ml/minute [range 23-58 ml/minute]) who received 400 mg/day HCQ, the median blood HCQ concentration was significantly higher than that in the 509 patients from the PLUS study (1,338 ng/ml [range 504-2,229 ng/ml] versus 917 ng/ml [range 208-3316 ng/ml]) (P < 0.001). CONCLUSION: We provide a comprehensive analysis of determinants of blood HCQ concentrations. Because this measurement is increasingly being used, these data might be useful for clinicians.

Role of the lean body mass and of pharmacogenetic variants on the pharmacokinetics and pharmacodynamics of sunitinib in cancer patients.

INTRODUCTION: Sunitinib is a multikinase inhibitor active in various cancers types including renal cancers and endocrine tumors. The study analyzed the influence of the lean body mass (LBM) and of pharmacogenetic variants on the exposure to sunitinib and its active metabolite, SU12662, and on sunitinib toxicity and clinical activity. MATERIALS AND METHODS: Exposure to sunitinib and SU12662 was assessed on days 10 and 21 during the first treatment cycle. Acute toxicity was graded using the NCI 4.0 CTCAE ver. 4.0. The LBM and 14 common single nucleotide polymorphisms in the CYP3A4/3A5, NR1I2, NR1I3, ABCB1, and ABCG2 genes were analyzed according to the drug exposure at day 10. Determinants (including sunitinib exposure and pharmacogenetic variants) for toxicities were assessed, as well as the relationship between drug exposure and survival in renal cancer patients. RESULTS: Ninety-two patients (60 % with renal cancer) were assessable for pharmacokinetics, toxicity and survival, and 66 for genetic analysis. The LBM (p < 0.0001) and a polymorphism in the ABCG2 transporter (421C>A) (p = 0.014) were two independent parameters accounting for the variability of composite (sunitinib + SU12662) exposure. Advanced age (OR = 1.47 [1.01-2.15], p = 0.048) and high sunitinib exposure (OR = 1.16 [1.05-1.28], p = 0.005) were independently associated with any grade ≥ 3 acute toxicity, and high SU12662 exposure was associated with grade ≥ 2 thrombocytopenia (OR = 1.27 [1.03-1.57], p = 0.028). A high composite area under the curve (AUC) >1,973 ng/mL∙h at day 21 was associated with a doubled survival (35.2 vs 16.7 months; log-rank p = 0.0051) in renal cancer patients. CONCLUSIONS: This study indicates that LBM and drug monitoring may be helpful in the management of sunitinib-treated patients.

Sorafenib in advanced melanoma: a critical role for pharmacokinetics?

BACKGROUND: Inter-patient pharmacokinetic variability can lead to suboptimal drug exposure, and therefore might impact the efficacy of sorafenib. This study reports long-term pharmacokinetic monitoring of patients treated with sorafenib and a retrospective pharmacodynamic/pharmacokinetic analysis in melanoma patients. PATIENTS AND METHODS: Heavily pretreated patients with stage IV melanoma were started on sorafenib 400 mg twice daily (bid). In the absence of limiting toxicity, dose escalation of 200 mg bid levels was done every 2 weeks. Plasma sorafenib measurement was performed at each visit, allowing a retrospective pharmacodynamic/pharmacokinetic analysis for safety and efficacy. RESULTS: In all, 19 of 30 patients underwent dose escalation over 400 mg bid, and 28 were evaluable for response. The overall disease control rate was 61% (95% confidence interval (CI): 42.6-78.8), including three confirmed responses (12%). Disease control rate and progression-free survival (PFS) were improved in patients with high vs low exposure (80% vs 32%, P=0.02, and 5.25 vs 2.5 months, P=0.005, hazard ratio (HR)=0.28 (95% CI: 0.11-0.73)). In contrast, drug dosing had no effect on PFS. In multivariate analysis, drug exposure was the only factor associated with PFS (HR=0.36 (95% CI: 0.13-0.99)). Diarrhoea and anorexia were correlated with drug dosing, while hypertension and hand-foot skin reaction were correlated with drug exposure. CONCLUSIONS: Although sorafenib had modest efficacy in melanoma, these results suggest a correlation between exposure and efficacy of sorafenib. Therefore, dose optimisation in patients with low exposure at standard doses should be evaluated in validated indications.

Mechanically-induced aggregation of the monoclonal antibody cetuximab.

This study focuses on the mechanically-induced aggregation of the anticancer monoclonal antibody cetuximab and its mechanism by comparing two commercially-available formulations (old formulation [OF]: 2mg/ml in phosphate buffer; new formulation [NF]: 5mg/ml in citrate buffer with polysorbate 80 and glycine). Cetuximab aggregation under stirring was followed during a 24h period and several methods were used to describe the aggregation kinetics (turbidimetry, size-exclusion high performance liquid chromatography, cation-exchange chromatography, dynamic light scattering and peptide mapping). Depending on the formulation, the aggregation process followed different kinetics: biexponential for the OF and mono-exponential for the NF. The percentage of aggregation after 24h stirring-period was about 25% for the OF but was only 2% for the NF corresponding to a ten-fold improvement, demonstrating a strong protecting effect of polysorbate and glycine. The aggregates are mainly due to an increased exposure of antibody molecules to air/liquid interface and are formed without chemical alteration of the antibody structure. This improvement of cetuximab stability by a new formulation seems linked to the stabilisation of cetuximab under dimeric form by a higher protein concentration and the presence of stabilizing excipients.

Validation of an HPLC-UV method for sorafenib determination in human plasma and application to cancer patients in routine clinical practice.

Sorafenib, a new oral multikinase inhibitor with antiangiogenic properties, has demonstrated preclinical and clinical activity against several tumor types. The aims of this study were to validate a method for the measurement of sorafenib in plasma from cancer patients, then to test this method in clinical practice. Following liquid-liquid extraction, the compounds were separated with gradient elution (on a C18 ultrasphere ODS column using a mobile phase of acetonitrile/20 mM ammonium acetate), then detected at 255 nm. The calibration was linear in the range 0.5-20 mg/L. Intra- and inter-assay precision was lower than 7 and 10%, respectively, at 0.5, 3 and 20 mg/L. Plasma sorafenib concentrations were measured in 22 cancer patients (99 samples). The mean trough sorafenib concentration (C(min)) and concentration at peak were 4.3+/-2.5 mg/L (n=68, CV=57.5%) and 6.2+/-3.0 mg/L (n=31, CV=47.5%), respectively. Mean sorafenib C(min) in eight patients who experienced grade 3 drug-related adverse events was approximately 1.5-fold greater than that observed in the remaining patients (7.7+/-3.6 mg/L vs. 4.4+/-2.4 mg/L, P=0.0083). In conclusion, the method was successfully used in routine practice to monitor plasma concentrations of sorafenib in cancer patients. Finally, large interindividual variability and higher exposure in patients experiencing severe toxicity support the need for therapeutic drug monitoring to ensure an optimal exposure to sorafenib.