Pharmacokinetics Of Docetaxel Research Articles

Darolutamide does not interfere with OATP-mediated uptake of docetaxel.

The addition of darolutamide, an androgen receptor signalling inhibitor, to therapy with docetaxel has recently been approved as a strategy to treat metastatic prostate cancer. OATP1B3 is an SLC transporter that is highly expressed in prostate cancer and is responsible for the accumulation of substrates, including docetaxel, into tumours. Given that darolutamide inhibits OATP1B3 in vitro, we sought to characterise the impact of darolutamide on docetaxel pharmacokinetics. We investigated the influence of darolutamide on OATP1B3 transport using in vitro and in vivo models. We assessed the impact of darolutamide on the tumour accumulation of docetaxel in a patient-derived xenograft (PDX) model and on an OATP1B biomarker in patients. Darolutamide inhibited OATP1B3 in vitro at concentrations higher than the reported Cmax. Consistent with these findings, in vivo studies revealed that darolutamide does not influence the pharmacokinetics of Oatp1b substrates, including docetaxel. Docetaxel accumulation in PDX tumours was not decreased in the presence of darolutamide. Metastatic prostate cancer patients had similar levels of OATP1B biomarkers, regardless of treatment with darolutamide. Consistent with a low potential to inhibit OATP1B3-mediated transport in vitro, darolutamide does not significantly impede the transport of Oatp1b substrates in vivo or in patients. Our findings support combined treatment with docetaxel and darolutamide, as no OATP1B3 transporter based drug-drug interaction was identified.

Impact of loperamide on the pharmacokinetics and tissue disposition of ritonavir-boosted oral docetaxel therapy; a preclinical assessment.

An oral docetaxel formulation boosted by the Cytochrome P450 (CYP) 3A inhibitor ritonavir, ModraDoc006/r, is currently under clinical investigation. Based on clinical data, the incidence of grade 1-2 diarrhea is increased with this oral docetaxel formulation compared to the conventional intravenous administration. Loperamide, a frequently used diarrhea inhibitor, could be added to the regimen as symptomatic treatment. However, loperamide is also a substrate of the CYP3A enzyme, which could result in competition between ritonavir and loperamide for this protein. Therefore, we were interested in the impact of coadministered loperamide on the pharmacokinetics of ritonavir-boosted oral docetaxel. We administered loperamide simultaneously or with an 8-hour delay to humanized CYP3A4 mice (with expression in liver and intestine) receiving oral ritonavir and docetaxel. Concentrations of docetaxel, ritonavir, loperamide and two of its active metabolites were measured. The plasma exposure (AUC and Cmax) of docetaxel was not altered during loperamide treatment, nor were the ritonavir plasma pharmacokinetics. However, the hepatic and intestinal dispositions of ritonavir were somewhat changed in the simultaneous, but not 8-hour loperamide treatment groups, possibly due to loperamide-induced delayed drug absorption. The pharmacokinetics of loperamide itself did not seem to be influenced by ritonavir. These results suggest that delayed loperamide administration can be added to ritonavir-boosted oral docetaxel treatment, without affecting the overall systemic exposure of docetaxel.

Application of Ganoderma lucidum extract for constructing an oral docetaxel delivery system

Docetaxel is one of the most valuable chemotherapeutic drugs, but it has extremely low oral bioavailability. In this study, an oral docetaxel delivery system was constructed based on the extract of Ganoderma lucidum, a well-known medicinal mushroom. First, a G. lucidum extract-docetaxel complex was prepared by stirring and freeze-drying. Results demonstrated that, compared to the docetaxel group, the exposure levels of docetaxel in the complex group were significantly increased in the mouse portal vein (Cmax, 599.7 vs. 58.5 ng/mL; AUC0–12 h, 631.2 vs. 185.9 ng·h/mL), systemic circulation (Cmax, 310.4 vs. 34.9 ng/mL; AUC0–12 h, 467.6 vs. 124.7 ng·h/mL), liver (Cmax, 431.2 vs. 58.4 ng/g liver; AUC0–12 h, 2007.3 vs. 473.0 ng·h/g liver), and lungs (Cmax, 1711.3 vs. 362.7 ng/g lung; AUC0–12 h, 5188.5 vs. 1329.5 ng·h/g lung). Moreover, in the complex group, except for metabolic stability (p > 0.05), transportation from the mucosal side of gut sacs to the serosal side (p < 0.01), solubility (52.6 vs. 4.2 μg/mL), and release of docetaxel in water were significantly improved (15 min, 5.5% vs. 2.3%; 8 h, 35.0% vs. 15.1%). Furthermore, scanning electron microscope (SEM), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD) analysis demonstrated the amorphous existing form of docetaxel. In conclusion, the pharmacokinetics of oral docetaxel in mice was improved by the G. lucidum extract-docetaxel complex, which changed the existing form of docetaxel from crystalline to amorphous. This study provides a simple solution to docetaxel’s low oral bioavailability.

Is Higher Docetaxel Clearance in Prostate Cancer Patients Explained by Higher CYP3A? An In Vivo Phenotyping Study with Midazolam.

Patients with prostate cancer (PCa) have a lower docetaxel exposure for both intravenous (1.8-fold) and oral administration (2.4-fold) than patients with other solid cancers, which could influence efficacy and toxicity. An altered metabolism by cytochrome P450 3A (CYP3A) due to castration status might explain the observed difference in docetaxel pharmacokinetics. In this in vivo phenotyping, pharmacokinetic study, CYP3A activity defined by midazolam clearance (CL) was compared between patients with PCa and male patients with other solid tumors. All patients with solid tumors who did not use CYP3A-modulating drugs were eligible for participation. Patients received 2 mg midazolam orally and 1 mg midazolam intravenously on 2 consecutive days. Plasma concentrations were measured with a validated liquid chromatography-tandem mass spectrometry method. Genotyping was performed for CYP3A4 and CYP3A5. Nine patients were included in each group. Oral midazolam CL was 1.26-fold higher in patients with PCa compared to patients with other solid tumors (geometric mean [coefficient of variation], 94.1 [33.5%] L/h vs 74.4 [39.1%] L/h, respectively; P= .08). Intravenous midazolam CL did not significantly differ between the 2 groups (P = .93). Moreover, the metabolic ratio of midazolam to 1'-hydroxy midazolam did not differ between the 2 groups for both oral administration (P = .67) and intravenous administration (P = .26). CYP3A4 and CYP3A5 genotypes did not influence midazolam pharmacokinetics. The observed difference in docetaxel pharmacokinetics between both patient groups therefore appears to be explained neither by a difference in midazolam CL nor by a difference in metabolic conversion rate of midazolam.

Phase 1 trial of bemcentinib (BGB324), a first-in-class, selective AXL inhibitor, with docetaxel in patients with previously treated advanced non-small cell lung cancer

ObjectivesAXL, a transmembrane receptor tyrosine kinase, is highly expressed and associated with poor prognosis in non-small cell lung cancer (NSCLC). Bemcentinib (BGB324), a selective orally bioavailable small molecule AXL inhibitor, synergizes with docetaxel in preclinical models. We performed a phase I trial of bemcentinib plus docetaxel in previously treated advanced NSCLC. Materials and MethodsEscalation of two dose levels of bemcentinib (200 mg load × 3 days then 100 mg daily, or 400 mg load × 3 days then 200 mg daily) in combination with docetaxel (60 or 75 mg/m2 every 3 weeks) followed a 3+3 study design. Due to hematologic toxicity, prophylactic G-CSF was added. Bemcentinib monotherapy was administered for one week prior to docetaxel initiation to assess pharmacodynamic and pharmacokinetic effects alone and in combination. Plasma protein biomarker levels were measured. Results21 patients were enrolled (median age 62 years, 67% male). Median treatment duration was 2.8 months (range 0.7–10.9 months). The main treatment-related adverse events were neutropenia (86%, 76% ≥G3), diarrhea (57%, 0% ≥G3), fatigue (57%, 5% ≥G3), and nausea (52%, 0% ≥G3). Neutropenic fever occurred in 8 (38%) patients. The maximum tolerated dose was docetaxel 60 mg/m2 with prophylactic G-CSF support plus bemcentinib 400 mg load × 3 days followed by 200 mg daily thereafter. Bemcentinib and docetaxel pharmacokinetics resembled prior monotherapy data. Among 17 patients evaluable for radiographic response, 6 (35%) patients had partial response and 8 (47%) patients had stable disease as best response. Bemcentinib administration was associated with modulation of proteins involved in protein kinase B signaling, reactive oxygen species metabolism, and other processes. ConclusionBemcentinib plus docetaxel with G-CSF support demonstrates anti-tumor activity in previously treated, advanced NSCLC. The role of AXL inhibition in the treatment of NSCLC remains under investigation.

Dosing, safety, and pharmacokinetics (PK) of combination therapy with darolutamide (DARO), androgen-deprivation therapy (ADT), and docetaxel (DOC) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) in the ARASENS study.

148 Background: In ARASENS (NCT02799602), DARO in combination with ADT and DOC significantly reduced the risk of death by 32.5% (HR 0.68; 95% CI 0.57–0.80; P&lt;0.001) vs placebo (PBO) + ADT + DOC in patients with mHSPC. Incidences of treatment-emergent adverse events (TEAEs) were similar between treatment groups. We report dosing, safety, and PK of coadministration of DARO and DOC with ADT. Methods: Patients with mHSPC were randomized 1:1 to DARO 600 mg twice daily or PBO, plus ADT and DOC (75 mg/m2 q21d for 6 cycles). The effect of DARO on DOC PK was assessed by noncompartmental analysis from the first 25 patients with dense PK data and by population PK (PopPK) for all patients. DARO PK from ARASENS were compared with PK data from ARAMIS (NCT02200614; without DOC) to evaluate the impact of DOC on DARO PK. Results: Of 1306 randomized patients, 1305 were included in the full analysis set (DARO, n=651; PBO, n=654). The median treatment duration was longer with DARO vs PBO (41.0 vs 16.7 months) and more DARO-treated patients (45.9% vs 19.1%) were still receiving treatment at primary analysis cutoff (Oct 25, 2021). Almost all patients completed 6 cycles of DOC in both groups (DARO, 87.6%; PBO, 85.5%). The proportion of patients requiring DOC dose modification (interrupted/delayed or reduced) was similar between groups (DARO, 60.0%; PBO, 62.9%). TEAEs led to discontinuation/reduction of DOC in 8.0%/19.9% of DARO patients and 10.3%/19.5% of PBO patients. PopPK analysis indicated that DOC PK in ARASENS was generally consistent with that in the literature. A slight numeric increase in DOC exposure was observed in the DARO + DOC + ADT arm, with 15% higher maximum plasma concentration (geometric mean, 1.93 vs 1.68 µg/mL) and 6% higher area under the concentration-time curve (AUC0-tlast within an 8-hour sampling interval, 2.10 vs 1.99 µg·h/mL) vs PBO + DOC + ADT. This small numeric increase is likely not clinically relevant given the variability in DOC exposure (coefficient of variation, 23%–54%). PK meta-analysis of ARASENS and, which considered patients’ intrinsic characteristics as covariates (eg, age, body weight, region), indicated a 10% lower AUC0-12ss of DARO in patients receiving DOC vs those not receiving DOC, which is not considered clinically relevant. Conclusions: The combination of DARO + DOC + ADT increases overall survival with similar overall incidence of TEAEs and no observed drug-drug interactions between DARO and DOC. DARO can be effectively and safely administered with DOC in patients with mHSPC without clinically relevant changes in PK of DARO or DOC. Clinical trial information: NCT02799602 .

Lean Body Mass and Total Body Weight Versus Body Surface Area as a Determinant of Docetaxel Pharmacokinetics and Toxicity.

This study examined whether anthropometric and body composition parameters such as body surface area (BSA), lean body mass (LBM), and total body weight (TBW) are correlated with docetaxel clearance and exposure by analyzing area under the curve. In addition, LBM, TBW, and a fixed dose were compared with BSA as dosing parameters for dose individualization of docetaxel. Thirty-six patients receiving docetaxel chemotherapy for breast or metastatic castration-resistant prostate carcinoma were included. Before treatment, LBM was measured using a dual-energy X-ray absorptiometry scanner. Blood samples were collected up to 180 minutes after dosing to analyze docetaxel concentrations and determine individual pharmacokinetic parameters. No significant correlations were found between docetaxel clearance and the anthropometric and body composition variables (BSA, LBM, and TBW). The area under the curve was significantly but poorly correlated with BSA [r = 0.452 ( P = 0.016)] and TBW [r = 0.476 ( P = 0.011)]. The mean absolute percentage error and mean error of simulated dosing based on LBM and fixed dosing were not significantly different from those of BSA. For TBW, only mean absolute percentage error was significantly higher compared with dosing based on BSA (24.1 versus 17.1, P = 0.001). There was no clinically relevant correlation between docetaxel pharmacokinetics and the anthropometric and body composition variables BSA, LBM, and TBW. Therefore, dose individualization of docetaxel based on LBM, TBW, or fixed dosing cannot be recommended over BSA-based dosing.

A pharmacometrics model to define docetaxel target in early breast cancer.

We aimed to study the relation between pharmacokinetics (PK) and pharmacodynamics (PD) of docetaxel in early breast cancer and recommend a target exposure. A PK/PD study was performed in 27 early breast cancer patients treated with doxorubicin and cyclophosphamide for 4 cycles followed by 4 cycles of docetaxel 75-100 mg/m2 infused every 21 days. Individual Bayesian estimates of docetaxel PK parameters were obtained using a nonparametric population PK model developed with data from patients with metastatic breast cancer who received dose-intensified docetaxel (300-350 mg/m2 ). Docetaxel area under the curve (AUC) and maximum concentration (Cmax) in each cycle and total cumulative AUC (AUCcum) were calculated and related to the incidence of adverse effects and tumour recurrence. Docetaxel clearance showed no change over the 4 treatment cycles, but a gradual increase in the volume of distribution was observed. One third of the patients had at least 1 dose reduction of docetaxel due to toxicity. The mean AUC, AUCcum and Cmax in patients showing docetaxel-associated adverse events were significantly higher than in patients free of toxicity (P < .05). Fatigue and decrease in haemoglobin and haematocrit levels were related to docetaxel AUC and Cmax and pain to AUC. AUC and Cmax >4.5mg*h/L and 3.5mg/L, respectively, were risk factors for docetaxel toxicity, while an AUC <4.5mg*h/L was associated with tumour recurrence. We report for the first time a relation between docetaxel exposure and toxicity and recommend specific targets of drug exposure with implications for the clinical management of early breast cancer patients.

Single-nucleotide polymorphisms and the effectiveness of taxane-based chemotherapy in premenopausal breast cancer: a population-based cohort study in Denmark

PurposeTaxane-based chemotherapy is the primary treatment for premenopausal breast cancer. Although being inconsistent, research suggests that variant alleles alter pharmacokinetics through reduced function of OATP transporters (limiting hepatic uptake), CYP-450 enzymes (hampering drug metabolism), and ABC transporters (decreasing clearance). Reduced function of DNA repair enzymes may hamper effectiveness through dose-limiting toxicities. We investigated whether single-nucleotide polymorphisms (SNPs) were associated with breast cancer recurrence or mortality in premenopausal women diagnosed with breast cancer.MethodsWe conducted a population-based cohort study of premenopausal women diagnosed with non-distant metastatic breast cancer in Denmark during 2007‒2011, when guidelines recommended adjuvant combination chemotherapy (taxanes, anthracyclines, and cyclophosphamide). Using archived formalin-fixed paraffin-embedded primary tumor tissue, we genotyped 26 SNPs using TaqMan assays. Danish health registries provided data on breast cancer recurrence (through September 25, 2017) and death (through December 31, 2019). We fit Cox regression models to calculate crude hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and mortality across genotypes.ResultsAmong 2,262 women, 249 experienced recurrence (cumulative incidence: 13%) and 259 died (cumulative incidence: 16%) during follow-up (median 7.0 and 10.1 years, respectively). Mortality was increased in variant carriers of GSTP1 rs1138272 (HR: 1.30, 95% CI 0.95–1.78) and CYP3A rs10273424 (HR: 1.33, 95% CI 0.98–1.81). SLCO1B1 rs2306283 (encoding OATP1B1) variant carriers had decreased recurrence (HR: 0.82, 95% CI 0.64–1.07) and mortality (HR: 0.77, 95% CI 0.60–0.98).ConclusionDocetaxel effectiveness was influenced by SNPs in GSTP1, CYP3A, and SLCO1B1 in premenopausal women with non-distant metastatic breast cancer, likely related to altered docetaxel pharmacokinetics. These SNPs may help determine individual benefit from taxane-based chemotherapy.

Comparison of docetaxel pharmacokinetics between castration-resistant and hormone-sensitive metastatic prostate cancer patients

PurposeRecently, docetaxel treatment of metastatic prostate cancer patients shifted towards the hormone-sensitive stage of the disease. There are contradictive reports on differences in toxicity of docetaxel in metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC) patients. Possible differences in toxicity might be attributed to different pharmacokinetics (PK) in the two patient populations.MethodsPatients with mCRPC or mHSPC and a standard indication for docetaxel treatment were included in the study. All patients had suppressed serum testosterone levels (≤ 0.5 ng/mL or 1.73 nmol/L). Venous blood samples were obtained at the first docetaxel treatment, until 48 h after infusion. Plasma concentrations of docetaxel, unbound docetaxel and docetaxel metabolites were measured using validated liquid chromatography coupled tandem mass spectrometry (LC–MS/MS) assays and compared between the two groups. Moreover, serum levels of docetaxel transporting α1-acid glycoprotein were measured and docetaxel toxicity recorded.ResultsA total of ten mCRPC and nine mHSPC patients were included in the study. The two cohorts differed in the number of prior treatments and opiate use, which were higher for mCRPC patients. The docetaxel PK was not different between mCRPC and mHSPC patients, with areas under the plasma concentration versus time curve (AUC0-48) 1710 [coefficient of variation (CV) 28.4%] and 1486 (CV 25.2%) ng/mL*h (p = 0.27), respectively. Also, the PK profile of unbound docetaxel, M1/M3, M2 and M4 metabolites were similar in both groups. Docetaxel doses were reduced in 50% of the mCRPC patients and 11% of the mHSPC patients.ConclusionThe PK profile of docetaxel was similar in mCPRC and mHSPC patients. Therefore, possible differences in toxicity between mCRPC and mHSPC patients cannot be explained by differences in docetaxel PK in our study population. These results suggest that treatment adaptations are not recommended in the new population of patients with mHSPC.

ADME gene polymorphisms do not influence the pharmacokinetics of docetaxel: Results from a population pharmacokinetic study in Indian cancer patients.

BackgroundPharmacokinetics (PK) of docetaxel is characterized by high inter‐individual variability (IIV). While covariate models that explain the PK variability of docetaxel exist, not much is known about the effects of genetic variations on docetaxel disposition.MethodsFifty patients with head and neck or prostate cancer were enrolled of whom two patients withdrew consent before the start of the study. Docetaxel was administered at either 50 or 75 mg/m2 as intravenous infusion over 1 h. One pharmacogenetic sample and a series of PK samples, either intensive (N = 5; 13 samples each) or sparse (N = 43; 6 samples each), were collected from each patient. Docetaxel levels were estimated using a validated HPLC method. Polymorphic loci on the Absorption, Distribution, Metabolism, and Elimination (ADME) genes were identified using the PharmacoScan array platform. Population pharmacokinetic analysis was carried out using NONMEM v7.2.ResultsDocetaxel PK was well characterized by a three‐compartment model. Clearance (Cl) was found to be 18 L/h with an IIV of 45.3%. None of the genetic variants showed significant covariate effect on the Cl of docetaxel. Patients with abnormal alanine aminotransferase (ALT) were found to have 25% lower Cl as compared to patients with normal ALT values. However, the covariate effect could not be established in the final model possibly due to lack of adequate number of patients with abnormal ALT.ConclusionGenetic polymorphisms in the ADME gene do not explain the IIV in PK of docetaxel. However, patients with abnormal liver function might require dose reduction.Clinical trial registration: Not applicable since participants in this study received treatment that was standard of care.

Pharmacokinetics of docetaxel and ritonavir after oral administration of ModraDoc006/r in patients with prostate cancer versus patients with other advanced solid tumours.

ModraDoc006 is a novel oral formulation of docetaxel. The clearance of intravenous docetaxel is higher in medically castrated prostate cancer patients as compared to patients with other types of solid tumours. Oral docetaxel requires co-administration ritonavir (r), which might further impact the pharmacokinetics (PK). We now compare the PK of docetaxel and ritonavir between patients with Hormone Sensitive Prostate Cancer (HSPC), metastatic Castration-Resistant Prostate Cancer (mCRPC) and other metastatic solid tumours, treated on the same dose and weekly schedule of ModraDoc006/r. The docetaxel and ritonavir PK were compared between four patient groups from three clinical phase I trials, including eight male and eight female patients with different types of solid tumours (study 1), seven patients with HSPC (study 2) and five patients with mCRPC (study 3). All patients were treated with ModraDoc006 30mg and ritonavir 100mg in the morning, followed by ModraDoc006 20mg and ritonavir 100mg in the evening (ModraDoc006/r 30-20/100-100). For comparative purposes, the PK of six mCRPC patients that received 30-20/200-100 in study 3 were also evaluated. The maximum plasma concentration (Cmax) was significantly lower for both docetaxel and ritonavir in the prostate cancer patients as compared to the patients with other types of solid tumours treated at ModraDoc006/r 30-20/100-100. The docetaxel area under the plasma concentration versus time curve (AUC) was significantly different at this dose, with a mean AUC0-48 of 1359 ± 374ng/mL*h (N = 8) in female patients and 894 ± 223ng/mL*h (N = 8) in male patients with different solid tumours (study 1), 321 ± 81 (N = 7) in HSPC (study 2) and 367 ± 182ng/mL*h (N = 5) in mCRPC (study 3). A similar pattern was observed for ritonavir. ModraDoc006/r 30-20/200-100 in six mCRPC patients led to a comparable ritonavir exposure as compared to the patients at 30-20/100-100 in study 1 and increased the docetaxel AUC0-48 to 1266 ± 473ng/mL*h (N = 6). The exposure to docetaxel and ritonavir was significantly lower in prostate cancer patients as compared to patients with other types of solid tumours, treated on ModraDoc006/r 30-20/100-100. An increase of the ritonavir dose increased the docetaxel exposure in mCRPC patients. Therefore, a different RP2D of ModraDoc006/r is pursued in castrated prostate cancer patients as compared to patients with other types of solid tumours. Study 1: ClinicalTrials.gov Identifier NCT01173913, date of registration August 2, 2010. Study 2: ClinicalTrials.gov Identifier NCT03066154, date of registration February 28, 2017. Study 3: ClinicalTrials.gov Identifier NCT03136640, date of registration May 2, 2017.

Investigating the influence of relevant pharmacogenetic variants on the pharmacokinetics and pharmacodynamics of orally administered docetaxel combined with ritonavir.

The anticancer drug docetaxel exhibits large interpatient pharmacokinetic and pharmacodynamic variability. In this study, we aimed to assess the functional significance of 14 polymorphisms in the CYP3A, CYP1B1, ABCB1, ABCC2, and SLCO1B3 genes for the pharmacokinetics and pharmacodynamics of oral docetaxel, co-administered with ritonavir. None of the tested CYP3A, ABCB1, ABCC2, and SLCO1B3 genotypes and diplotypes showed a significant relation with an altered bioavailability or clearance of either docetaxel or ritonavir. Similarly, no clear effect of CYP1B1 genotype on clinical outcomes was observed in a subgroup of non-small cell lung cancer (NSCLC) patients. Our post hoc power analysis indicated that our pharmacogenetic-pharmacokinetic analysis was only powered for relatively high effect sizes, which were to be expected given the high interpatient variability. This makes it unlikely that future studies will explain the high observed interpatient variability in oral docetaxel pharmacokinetics as a result of any of these separate polymorphisms and diplotypes.

SAPROCAN: Saracatinib (AZD0530) and docetaxel in metastatic,castrate-refractory prostate cancer (mCRPC)—A phase I/randomized phase II study by the United Kingdom National Cancer Research Institute Prostate Group.

107 Background: Saracatinib is an orally-available, highly selective inhibitor of Abl and Src family members. It is an ATP-competitive tyrosine kinase inhibitor. Preclinical data suggested that the combination of a Src kinase inhibitor and docetaxel is synergistic, and Src kinase activity was also implicated in the bone’s metabolic response to cancer metastases. Methods: Patients with mCRPC were initially enrolled in an open-label, dose escalation phase I trial of oral saracatinib (cohorts of 50mg, 125mg and 175mg daily) with docetaxel (75mg/m2) in a 3+3 design. Subsequent patients were randomised 1:1 between saracatinib 175mg and placebo once daily. Pharmacokinetics (PK) of docetaxel were explored in phase I to exclude significant drug-drug interaction. The primary endpoint of phase II was biochemical or radiographic progression free survival (PFS). Secondary endpoints included overall survival (OS), safety and tolerability. Changes in circulating tumour cell (CTC) counts were also measured. The phase II was designed with a 1-sided alpha of 0.2 with 90% power to detect a hazard ratio (HR) for PFS of 0.67. Results: 10 patients were enrolled in phase I and 142 in the randomised phase II. No dose limiting toxicities or PK interactions were observed and the recommended dose for phase II was 175mg saracatinib daily and 75mg/m2docetaxel every 21 days. In phase II, the HR for PFS was 1.35 (80% confidence interval (CI) 1.07 to 1.70). The HR for OS was 1.42 (1.08 – 1.81). 41/71 and 29/71 experienced treatment related toxicities of grade 3 or above in the saracatinib and placebo arms respectively. 10/19 (53%) and 14/27 (52%) evaluable patients demonstrated a reduction in CTCs from ≥5 to &lt; 5 /7.5ml blood at 6 weeks after starting saracatinib and placebo respectively. Conclusions: Saracatinib, in combination with docetaxel, adds toxicity and not efficacy in mCRPC. This combination should not be developed further in combination with docetaxel in the treatment of mCRPC. Clinical trial information: ISRCTN22566729.

Population Pharmacokinetics of Docetaxel, Paclitaxel, Doxorubicin and Epirubicin in Pregnant Women with Cancer: A Study from the International Network of Cancer, Infertility and Pregnancy (INCIP).

Based on reassuring short-term foetal and maternal safety data, there is an increasing trend to administer chemotherapy during the second and third trimesters of pregnancy. The pharmacokinetics (PK) of drugs might change as a result of several physiological changes that occur during pregnancy, potentially affecting the efficacy and safety of chemotherapy. With this analysis, we aimed to quantitatively describe the changes in the PK of docetaxel, paclitaxel, doxorubicin and epirubicin in pregnant women compared with non-pregnant women. PK data from 9, 20, 22 and 16 pregnant cancer patients from the International Network of Cancer, Infertility and Pregnancy (INCIP) were available for docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. These samples were combined with available PK data from non-pregnant patients. Empirical non-linear mixed-effects models were developed, evaluating fixed pregnancy effects and gestational age as covariates. Overall, 82, 189, 271, and 227 plasma samples were collected from pregnant patients treated with docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. The plasma PK data were adequately described by the respective models for all cytotoxic drugs. Typical increases in central and peripheral volumes of distribution of pregnant women were identified for docetaxel, paclitaxel, doxorubicin and epirubicin. Additionally, docetaxel, doxorubicin and paclitaxel clearance were increased in pregnant patients, resulting in lower exposure in pregnant women compared with non-pregnant patients. Given the interpatient variability, the identified pregnancy-induced changes in PK do not directly warrant dose adjustments for the studied drugs. Nevertheless, these results underscore the need to investigate the efficacy of chemotherapy, when administered during pregnancy.

ABCB1 and ABCC2 genetic polymorphism as risk factors for neutropenia in esophageal cancer patients treated with docetaxel, cisplatin, and 5-fluorouracil chemotherapy.

The combination of docetaxel, cisplatin and 5-fluorouracil (DCF) is a newly developed chemotherapy regimen for esophageal cancer. Severe neutropenia is dose-limiting toxicity of docetaxel and it is well known to be frequently occurred during DCF chemotherapy. This study aimed to investigate the relationship between severe neutropenia and genetic polymorphisms in patients treated with preoperative DCF chemotherapy. A total of 158 patients were investigated for their absolute neutrophil count (ANC) within the first cycle of DCF chemotherapy at the National Cancer Center (NCC) Hospital East. DNA samples obtained from the NCC Biobank Registry were used for the analysis of nine genetic polymorphisms related to docetaxel pharmacokinetics. These genotypes were evaluated for their association with severe neutropenia, and further their risk factors were examined using a multivariate logistic regression. A total 81 (51.3%) patients developed severe neutropenia. Multivariate analysis revealed that age (OR 1.054; CI 1.008-1.102, P = 0.022), baseline ANC (OR 1.019; CI 1.002-1.037, P = 0.030), ABCB1 3435C>T (OR 2.191; CI 1.087-4.417, P = 0.028) and ABCC2 *+9383C>G (OR 2.342; CI 1.108-4.948, P = 0.026) were significant risk factors for severe neutropenia development. The results from this study showed that age, ANC, ABCB1 3435C>T, and ABCC2 *+9383 G>C increased the incidence of severe neutropenia with the number of identified risk factors. In addition to age and baseline ANC, ABCB1 3435C>T and ABCC2 *+9383C>G were identified as independent predictors for severe neutropenia in esophageal cancer patients treated with DCF chemotherapy.

Exposure to Docetaxel in the Elderly Patient Population: a Population Pharmacokinetic Study.

Docetaxel is commonly used in elderly patients, who are frequently diagnosed with prostate cancer. Although previous studies revealed no clinically relevant impact of older age on docetaxel pharmacokinetics (PK), this may be masked by indication. Metastatic castration-resistant prostate cancer (mCRPC) patients were reported to have approximately two-times lower systemic exposure compared to patients with other solid tumors. This study assessed the impact of older age on docetaxel PK, also considering the effect of indication on docetaxel PK. Prospectively collected docetaxel PK data from patients aged ≥70 was pooled with PK data from an earlier published multicenter study. A 3-compartment population PK model, including multiple covariates, was used to describe docetaxel plasma concentration-time data. We added the effect of prostate cancer (mCRPC and metastatic hormone-sensitive prostate cancer (mHSPC)) on clearance to this model. Hereafter, we evaluated the additional impact of older age on docetaxel clearance, using a significance threshold of p < 0.005. Docetaxel plasma concentration-time data from 157 patients were analyzed. Median age in the total cohort was 67years (range 31-87), with 49% of the total cohort aged ≥70. The impact of age on docetaxel clearance was statistically significant (p < 0.005). For a typical patient, a 10-year and 20-year increase of age led to a reduction in clearance of 17% and 34%, respectively. In this cohort study, age significantly and independently affected docetaxel clearance, showing lower docetaxel clearance in elderly patients. In our cohort, mCRPC and mHSPC patients both had higher clearance than patients with other solid tumors.

487P - Comparison of intratumoral docetaxel exposure in cancer patients between nanoparticle entrapped docetaxel (CPC634) and conventional docetaxel (Cd): The CriTax study

BackgroundIneffective chemotherapy may partly be caused by subtherapeutic intratumoral drug levels. Nanomedicines are developed to improve the therapeutic index, by increasing intratumoral drug exposure and preserving healthy tissue. CPC634 is a new nanoparticle entrapping docetaxel. Here, we hypothesized that CPC634 increases intratumoral docetaxel level and overall duration of exposure. MethodsIn this randomized cross-over study we assessed both plasma and intratumoral pharmacokinetics (PK) of docetaxel after intravenous administration of 75mg/m2 conventional docetaxel (Cd) and CPC634. We aimed to identify a 25% increase of intratumoral docetaxel exposure after CPC634 infusion compared to Cd. Adult patients were randomized to receive Cd in cycle 1 and CPC634 in cycle 2 or vice versa. Tumor biopsies were taken 24, 48, 72, 96, 168 or 336hours after infusion during both cycles. Total docetaxel concentration (TDC) was determined for both drugs and released docetaxel for CPC634 in tumor tissue and plasma. PK data were analyzed using mixed modeling. ResultsIn total, 21 evaluable patients were included. In plasma, the area under the curve (AUCinf) of released docetaxel was higher (+27%, 95% CI: 11-44%, P=0.001) while peak plasma concentration (Cmax) (-91%, 95% CI: -92:-89%, P<0.001) and clearance (-21%, 95% CI: -31;-10%, P=0.001) decreased during CPC634 administration versus Cd. Intratumoral TDC was 375% higher (95% CI: 187-686%, P<0.001) after CPC634 administration, while released docetaxel was comparable to Cd (+8%, 95% CI: -30-+69%, P=0.71). ConclusionsThe plasma PK profile of CPC634 is favorable compared to Cd since a lower Cmax, lower clearance and prolonged higher systemic exposure is seen. Higher intratumoral TDC levels were reached with CPC634, while released docetaxel levels were comparable to Cd. The almost 4-fold increased tumor accumulation for prolonged period of time of TDC supports the expectation that CPC634 will exhibit beneficial efficacy/safety balance. Additional studies assessing the intratumoral exposure to CPC634 (NCT0371243) and a phase II efficacy study of CPC634 in platinum resistant ovarian cancer patients (NCT03742713) are currently ongoing. Clinical trial identificationNetherlands Trial Registry NL6299 (NTR6474). Legal entity responsible for the studyProf. Dr. A.H.J. Mathijssen as principle investigator. FundingCristal Therapeutics. DisclosureC.J.F. Rijcken: Officer / Board of Directors: Cristal Therapeutics; Leadership role: Cristal Therapeutics; Shareholder / Stockholder / Stock options: Cristal Therapeutics; Full / Part-time employment: Cristal Therapeutics. R. Hanssen: Full / Part-time employment: Cristal Therapeutics. R.H.J. Mathijssen: Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Boehringer; Research grant / Funding (institution): Cristal Therapeutics; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pamgene; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi; Honoraria (institution): Servier; Honoraria (institution): Novartis; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Astellas. S.L. Koolen: Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Roche; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Cristal Therapeutics; Travel / Accommodation / Expenses: Ipsen. All other authors have declared no conflicts of interest.

Nanoparticle entrapped docetaxel (CPC634) enhances intratumoral docetaxel exposure compared to conventional docetaxel (Cd) in patients with solid tumors.

3096 Background: Failure or resistance to chemotherapy may be caused by sub‐therapeutic intratumoral drug levels. Nanomedicine aim to improve intratumoral drug exposure. CPC634 is a nanoparticle entrapping docetaxel. We hypothesized that CPC634 increases intratumoral docetaxel exposure. Methods: In this randomized cross-over study we assessed intratumoral and plasma pharmacokinetics (PK) of docetaxel after intravenous administration of CPC634 and conventional docetaxel (Cd). The study was powered to identify an 25% increase in intratumoral docetaxel exposure of CPC634 relative to Cd. Patients (≥18 years) were randomized to receive 75 mg/m2 CPC634 in cycle 1 and Cd in cycle 2 or vice versa. After drug administration, patients underwent tumor biopsies during both cycles. Total docetaxel was determined for both drugs and released docetaxel for CPC634 in tumor tissue and in plasma with a validated LC-MS/MS method. PK data were analyzed with mixed model analysis. Results: Sixteen evaluable patients were included. Intratumoral PK revealed a 323% (95% CI: 148,621) higher total docetaxel (p &lt; 0.001) for CPC634. Released docetaxel for CPC634 was comparable to total docetaxel levels for Cd (95% CI: -35-,67) (p = 0.43). Plasma released docetaxel for CPC634 exhibited an 89% (95% CI: 86, 91) lower (p &lt; 0.001) peak plasma concentration (Cmax) and 81% (95% CI: 46, 125) higher (p &lt; 0.001) area under the curve (AUC) relative to Cd. Conclusions: CPC634 resulted in higher intratumoral total docetaxel and comparable released docetaxel levels relative to total docetaxel for Cd. CPC634 had a favorable plasma PK profile with a lower Cmax and prolonged higher systemic exposure relative to Cd. These results indicate that CPC634 could improve intratumoral docetaxel exposure compared to Cd. Additional studies assessing the intratumoral exposure to CPC634 (NCT0371243) and a phase II efficacy study of CPC634 in patients with platinum resistant ovarian cancer (NCT03742713) are currently ongoing.

Effects of prednisone on docetaxel pharmacokinetics in men with metastatic prostate cancer: A randomized drug-drug interaction study.

Docetaxel has been approved for the treatment of metastatic prostate cancer in combination with prednisone. Since prednisone is known to induce the cytochrome P450 iso-enzyme CYP3A4, which is the main metabolizing enzyme of docetaxel in the liver, a potential drug-drug interaction may occur. In this prospective randomized pharmacokinetic cross-over study we investigated docetaxel exposure with concomitant prednisone, compared to docetaxel monotherapy in men with metastatic prostate cancer. Patients scheduled to receive at least 6cycles of docetaxel (75mg/m2 ) and who gave written informed consent were randomized to receive either the 1st 3cycles, or the last 3 consecutive cycles with prednisone (twice daily 5mg). Pharmacokinetic blood sampling was performed during cycle 3 and cycle 6. Primary endpoint was difference in docetaxel exposure, calculated as area under the curve (AUC0-inf ) and analysed by means of a linear mixed model. Given the cross-over design the study was powered on 18 patients to answer the primary, pharmacokinetic, endpoint. Eighteen evaluable patients were included in the trial. Docetaxel concentration with concomitant prednisone (AUC0-inf 2784ng*h/mL, 95% confidence interval 2436-3183ng*h/mL) was similar to the concentration of docetaxel monotherapy (AUC0-inf 2647ng*h/mL, 95% confidence interval 2377-2949ng*h/mL). Exploratory analysis showed no toxicity differences between docetaxel monotherapy and docetaxel cycles with prednisone. No significant difference in docetaxel concentrations was observed. In addition, we found similar toxicity profiles in absence and presence of prednisone. Therefore, from a pharmacokinetic point of view, docetaxel may be administrated with or without prednisone.