Role of the efflux transporters Abcb1 and Abcg2 in the brain distribution of olaparib in mice.

Olaparib is a first-in-class poly (ADP-ribose) polymerase oral inhibitor used to treat various tumors. In this study, we clarified the roles of ABCB1/Abcb1 and ABCG2/Abcg2 transporters in restricting olaparib distribution to the brain. Olaparib was efficiently transported by human ABCG2, human ABCB1, and mouse Abcg2 in vitro. In the in vivo disposition study of olaparib using single or combination knockout mice, the systemic exposure of olaparib did not differ significantly between the strains over an 8-h period. However, the brain-to-plasma unbound concentration ratio of olaparib increased 5.6- and 8.1-fold in Abcb1a/1b and Abcb1a/1b;Abcg2 knockout mice, respectively, compared with wild-type mice. The Abcg2 single knockout mice exhibited a similar brain-to-plasma unbound concentration ratio to wild-type mice. Moreover, the brain distribution of olaparib could be modulated by the ABCB1/ABCG2 dual inhibitor elacridar to reach a similar degree of inhibition to Abcb1a/1b-/-. These findings suggest that olaparib is actively transported by both human and mouse ABCB1/Abcb1 and ABCG2/Abcg2; while Abcb1a/1b is a major determinant of olaparib brain penetration in mice, Abcg2 is likely to be a minor contributor. Concomitant treatment with temozolomide slightly increased the brain distribution of olaparib in mouse, but the clinical impact of the interaction was expected to be limited.

Evaluation of pharmacokinetics and safety of talazoparib in patients with advanced cancer and varying degrees of hepatic impairment.

AIM: This phase I study investigated talazoparib pharmacokinetics (PK) and safety in patients with advanced solid tumours and varying degrees of hepatic function. METHODS: Patients with advanced solid tumours and normal hepatic function or varying degrees of hepatic impairment (mild, moderate or severe, based on National Cancer Institute Organ Dysfunction Working Group classification) received talazoparib 0.5 mg once daily for 22 calendar days. Plasma and urine samples after single and multiple doses were collected and analysed for talazoparib using validated assays. Plasma PK data from all patients were analysed using the population PK method. Plasma and urine PK parameters in PK-evaluable patients were calculated using noncompartmental analysis (NCA). Safety was monitored in all enrolled patients. RESULTS: Thirty-eight patients were enrolled; 37 had ≥1 PK concentration, among which 17 were evaluable for NCA. Population PK analysis (n = 37) indicated no significant impact of hepatic function on apparent clearance (CL/F) of talazoparib. Baseline creatinine clearance was the only significant covariate on CL/F (α = 0.05). NCA of data (n = 17) showed no clear trend for increase in exposure on day 22 with worsening hepatic function. Talazoparib protein binding was comparable in patients with varying hepatic function. Talazoparib was generally well tolerated, and the safety profile observed in this study was consistent with the known safety profile of the drug. CONCLUSIONS: Hepatic impairment (mild, moderate or severe) has no impact on the PK of talazoparib. No dose modification is recommended for patients with advanced solid tumours and various degrees of hepatic impairment, and this labelling language has been approved by the US Food and Drug Administration and the European Medicines Agency.

Safety, pharmacokinetics, and preliminary efficacy of the PARP inhibitor talazoparib in Japanese patients with advanced solid tumors: phase 1 study.

BACKGROUND: Talazoparib is a poly(ADP-ribose) polymerase enzyme inhibitor. This open-label, non-randomized, phase 1 study of talazoparib investigated the safety, pharmacokinetics, and preliminary antitumor activity in Japanese patients with locally advanced or metastatic solid tumors, regardless of mutations in DNA damage repair-related genes, who are resistant to/ineligible for standard therapies. METHODS: Patients received talazoparib dosed orally at 0.75 or 1 mg once daily using a modified 3 + 3 dose-escalation scheme. Primary endpoint was dose-limiting toxicities during the first cycle of talazoparib. RESULTS: Nine patients (median age 62.0 years) were included: 3 and 6 patients at the 0.75 and 1.0 mg once-daily dose levels, respectively. No dose-limiting toxicities were reported. The most commonly reported treatment-emergent adverse events (≥2 patients) were anemia, stomatitis, maculopapular rash, platelet count decreased, neutrophil count decreased, and alanine aminotransferase increased. Three patients had grade ≥ 3 treatment-emergent adverse events (anemia, brain metastases [1 patient each], and neutrophil and white blood cell count decreased [same patient]). Two patients temporarily discontinued treatment due to a treatment-emergent adverse event, and 1 patient required a dose reduction for neutrophil count decreased (all at 1 mg once daily). Talazoparib exposure (Cmax and AUC) after single and multiple dosing was slightly higher proportionally with talazoparib 1 mg than talazoparib 0.75 mg. The overall disease control rate was 44.4%, including 2 patients with stable disease. The recommended phase 2 dose of talazoparib was established as 1 mg once daily. CONCLUSIONS: Single-agent talazoparib was well tolerated and had preliminary antitumor activity in Japanese patients with advanced solid tumors. ClinicalTrials.gov identifier: NCT03343054 (November 17, 2017).

ADMETlab 2.0: an integrated online platform for accurate and comprehensive predictions of ADMET properties.

Because undesirable pharmacokinetics and toxicity of candidate compounds are the main reasons for the failure of drug development, it has been widely recognized that absorption, distribution, metabolism, excretion and toxicity (ADMET) should be evaluated as early as possible. In silico ADMET evaluation models have been developed as an additional tool to assist medicinal chemists in the design and optimization of leads. Here, we announced the release of ADMETlab 2.0, a completely redesigned version of the widely used AMDETlab web server for the predictions of pharmacokinetics and toxicity properties of chemicals, of which the supported ADMET-related endpoints are approximately twice the number of the endpoints in the previous version, including 17 physicochemical properties, 13 medicinal chemistry properties, 23 ADME properties, 27 toxicity endpoints and 8 toxicophore rules (751 substructures). A multi-task graph attention framework was employed to develop the robust and accurate models in ADMETlab 2.0. The batch computation module was provided in response to numerous requests from users, and the representation of the results was further optimized. The ADMETlab 2.0 server is freely available, without registration, at https://admetmesh.scbdd.com/.

A phase I dose-finding, pharmacokinetics and genotyping study of olaparib and lurbinectedin in patients with advanced solid tumors.

The poly (ADP-Ribose) polymerase (PARP) inhibitor olaparib has shown antitumor activity in patients with ovarian or breast cancer with or without BRCA1/2 mutations. Lurbinectedin is an ecteinascidin that generates DNA double-strand breaks. We hypothesized that the combination of olaparib and lurbinectedin maximizes the DNA damage increasing the efficacy. A 3 + 3 dose-escalation study examined olaparib tablets with lurbinectedin every 21 days. The purpose of this phase I study is to determine the dose-limiting toxicities (DLTs) of the combination, to investigate the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), efficacy, pharmacokinetics, in addition to genotyping and translational studies. In total, 20 patients with ovarian and endometrial cancers were included. The most common adverse events were asthenia, nausea, vomiting, constipation, abdominal pain, neutropenia, anemia. DLT grade 4 neutropenia was observed in two patients in dose level (DL) 5, DL4 was defined as the MTD, and the RP2D was lurbinectedin 1.5 mg/m2 + olaparib 250 mg twice a day (BID). Mutational analysis revealed a median of 2 mutations/case, 53% of patients with mutations in the homologous recombination (HR) pathway. None of the patients reached a complete or partial response; however, 60% of stable disease was achieved. In conclusion, olaparib in combination with lurbinectedin was well tolerated with a disease control rate of 60%. These results deserve further evaluation of the combination in a phase II trial.

Pharmacokinetic effects of proton pump inhibitors on the novel PARP inhibitor fluzoparib: a single-arm, fixed-sequence trial in male healthy volunteers.

Purpose To assess the pharmacokinetic (PK) effect of proton pump inhibitors on the novel poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor fluzoparib, and observe the safety of its co-administration with omeprazole. Patients and methods Sixteen male healthy volunteers (HVs) were enrolled in a single-center, single-arm, open-label, fixed-sequence study. HVs took fluzoparib (100 mg, p.o.) after meal consumption on day-1, took omeprazole 40 mg (p.o.) under a fasting condition from day-5 to day-9, and took fluzoparib (100 mg, p.o.) after meal consumption on day-9. Blood samples were collected at predetermined timepoints for PK analyses. Safety was assessed via clinical laboratory tests. The study was registered with the Clinical Trials Registry on 30 September 2019 (NCT04108676). Results The peak plasma concentrations (Cmax) after fluzoparib administration was 2395.17 ± 418.27 ng/mL, the area under the curve (AUC) within 72 h (AUC0 - 72 h) was 26669.09 ± 7320.12 h·ng/mL, and AUC0-∞ was 26897.44 ± 7573.61 h·ng/mL. The Cmax after co-administration of fluzoparib and omeprazole was 2489.43 ± 423.72 ng·mL, AUC0 - 72 h was 30300.49 ± 8350.08 h·ng/mL, and AUC0-∞ was 30678.74 ± 8595.55 h·ng/mL. The geometric mean ratio of Cmax, AUC0 - 72 h and AUC0-∞ was 104.0% (90%CI: 94.8-114.0%), 113.6% (104.2-123.9%) and 104.1% (104.5-124.6%). The number of HVs with adverse reactions was identical (eight) for administration of fluzoparib and co-administration of fluzoparib and omeprazole. Conclusions The proton pump inhibitor omeprazole did not have a significant influence on the PK behavior of fluzoparib, and its safety profile was good upon co-administration with omeprazole. (NCT04108676, 30 September 2019).

FBI-1 enhanced the resistance of triple-negative breast cancer cells to chemotherapeutic agents via the miR-30c/PXR axis.

The factor that binds to the inducer of short transcripts-1 (FBI-1) is a transcription suppressor and an important proto-oncogene that plays multiple roles in carcinogenesis and therapeutic resistance. In the present work, our results indicated that FBI-1 enhanced the resistance of triple-negative breast cancer (TNBC) cells to chemotherapeutic agents by repressing the expression of micoRNA-30c targeting the pregnane X receptor (PXR). The expression of FBI-1 was positively related to PXR and its downstream drug resistance-related genes in TNBC tissues. FBI-1 enhanced the expression of PXR and enhanced the activation of the PXR pathway. The miR-30c decreased the expression of PXR by targeting the 3'-UTR of PXR, and FBI-1 increased the expression of PXR by repressing miR-30c's expression. Through the miR-30c/PXR axis, FBI-1 accelerated the clearance or elimination of antitumor agents in TNBC cells (the TNBC cell lines or the patients derived cells [PDCs]) and induced the resistance of cells to antitumor agents. Therefore, the results indicated that the miR-30c/PXR axis participates in the FBI-1-mediated drug-resistance of TNBC cells.

Hit-to-lead optimization and discovery of a potent, and orally bioavailable G protein coupled receptor kinase 2 (GRK2) inhibitor.

G-protein coupled receptor kinase 2 (GRK2), which is upregulated in the failing heart, appears to play a critical role in heart failure (HF) progression in part because enhanced GRK2 activity promotes dysfunction of ß-adrenergic signaling and myocyte death. An orally bioavailable GRK2 inhibitor could offer unique therapeutic outcomes that cannot be attained by current heart failure treatments that directly target GPCRs or angiotensin-converting enzyme. Herein, we describe the discovery of a potent, selective, and orally bioavailable GRK2 inhibitor, 8h, through high-throughput screening, hit-to-lead optimization, structure-based design, molecular modelling, synthesis, and biological evaluation. In the cellular target engagement assays, 8h enhances isoproterenol-mediated cyclic adenosine 3',5'-monophosphate (cAMP) production in HEK293 cells overexpressing GRK2. Compound 8h was further evaluated in a human stem cell-derived cardiomyocyte (HSC-CM) contractility assay and potentiated isoproterenol-induced beating rate in HSC-CMs.

Population pharmacokinetic analysis of nanoparticle-bound and free camptothecin after administration of NLG207 in adults with advanced solid tumors.

PURPOSE: NLG207 (formerly CRLX101) is a nanoparticle-drug conjugate (NDC) of the potent topoisomerase I inhibitor, camptothecin (CPT). The present study sought to characterize the complex pharmacokinetics (PK) of NLG207 and better describe CPT release from nanoparticles using a population PK (popPK) model. METHODS: From 27 patients enrolled on two phase II clinical trials (NCT02769962 and NCT03531827), dense sampling was performed up to 48 h post-administration of NLG207 during cycle one and six of treatment; samples were also collected at ~ 360 h post-dose. Conjugated and free CPT concentrations were quantified from each sample, resulting in 477 observations to build a popPK model using non-linear mixed-effects modeling. RESULTS: The PK of NLG207 was characterized by combining two linear two-compartment models with first-order kinetics each to describe nanoparticle-bound (conjugated) and free CPT. Allometric scaling based on body weight provided the best body-size descriptor for all PK parameters. The typical volumes of distribution of the conjugated CPT central and free CPT central compartments were 3.16 L (BSV CV%; 18.1%) and 21.1 L (CV%; 79.8%), respectively. CPT release from the nanoparticle formulation was characterized via an initial rapid clearance of 5.71 L/h (CV%; 62.6%), which decreased via first-order decay (estimated half-life of 0.307 h) to the steady-state value of 0.0988 L/h (CV%; 33.5%) by ~ 4 h after end of infusion. Renal clearance of free CPT was 0.874 L/h (CV%; 42.2%). CONCLUSION: The popPK model confirmed nanoparticle behavior of conjugated CPT and mechanistically characterized CPT release from NLG207. The current analysis provides a strong foundation for future study as a potential predictive tool in ongoing NLG207 clinical trials.

Exposure-Safety Analyses of Talazoparib in Patients With Advanced Breast Cancer and Germline BRCA1/2 Mutations in the EMBRACA and ABRAZO Trials.

Poly(ADP-ribose) polymerase inhibitors, such as talazoparib, may affect hematopoiesis. This analysis characterized the relationship between talazoparib exposure and the most common grade ≥ 3 hematopoietic adverse events (AEs) leading to dose modification in the phase 2 (ABRAZO) and phase 3 (EMBRACA) trials. The relationship between time-varying average talazoparib concentration (Cavg,t ), along with other baseline variables, and grade ≥ 3 anemia, thrombocytopenia, and neutropenia were evaluated both by graphical examination and using univariate and multivariate Cox proportional hazard models. The results indicated that higher Cavg,t was associated with a higher risk of anemia and thrombocytopenia. A trend toward an association between higher Cavg,t and neutropenia was observed, although not statistically significant. Higher risk of all tested safety end points was associated with lower baseline hemoglobin. Higher risk of neutropenia was associated with lower baseline absolute neutrophil count and lower body weight. These findings support the proposed management of AEs through talazoparib dosing modification.

Quantitative determination of niraparib and olaparib tumor distribution by mass spectrometry imaging.

Rationale: Optimal intratumor distribution of an anticancer drug is fundamental to reach an active concentration in neoplastic cells, ensuring the therapeutic effect. Determination of drug concentration in tumor homogenates by LC-MS/MS gives important information about this issue but the spatial information gets lost. Targeted mass spectrometry imaging (MSI) has great potential to visualize drug distribution in the different areas of tumor sections, with good spatial resolution and superior specificity. MSI is rapidly evolving as a quantitative technique to measure the absolute drug concentration in each single pixel. Methods: Different inorganic nanoparticles were tested as matrices to visualize the PARP inhibitors (PARPi) niraparib and olaparib. Normalization by deuterated internal standard and a custom preprocessing pipeline were applied to achieve a reliable single pixel quantification of the two drugs in human ovarian tumors from treated mice. Results: A quantitative method to visualize niraparib and olaparib in tumor tissue of treated mice was set up and validated regarding precision, accuracy, linearity, repeatability and limit of detection. The different tumor penetration of the two drugs was visualized by MSI and confirmed by LC-MS/MS, indicating the homogeneous distribution and higher tumor exposure reached by niraparib compared to olaparib. On the other hand, niraparib distribution was heterogeneous in an ovarian tumor model overexpressing the multidrug resistance protein P-gp, a possible cause of resistance to PARPi. Conclusions: The current work highlights for the first time quantitative distribution of PAPRi in tumor tissue. The different tumor distribution of niraparib and olaparib could have important clinical implications. These data confirm the validity of MSI for spatial quantitative measurement of drug distribution providing fundamental information for pharmacokinetic studies, drug discovery and the study of resistance mechanisms.

Pharmacological issues concerning olaparib capsule and tablet formulations in treating ovarian cancer: Are they really the same drug?

Olaparib is a first-in-class PARP inhibitor that has demonstrated efficacy as maintenance therapy in patients with ovarian cancer. It has been approved as a capsule formulation and after the publication of data from SOLO2 study became available also as tablet formulation. Due to different pharmacokinetic properties, these different formulations cannot be considered bioequivalent nor interchangeable. The tablet formulation has improved bioavailability, reducing pill burden and offering a more convenient dosage regimen. Furthermore, olaparib tablet formulation had a manageable tolerability profile if compared to capsule one, with most of adverse events of mild or moderate severity. Under this light, olaparib tablet formulation is a useful maintenance strategy for recurrent, platinum-sensitive ovarian cancer, providing a more convenient dosing option than the capsule formulation.

Gender-dependent pharmacokinetics of olaparib in rats determined by ultra-high performance liquid chromatography/electrospray ionization tandem mass spectrometry.

The aim of the present study was to develop a liquid chromatography/electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) method for the determination of olaparib in rat plasma. The plasma samples were processed using one-step protein precipitation with acetonitrile and then separated on Waters Acquity BEH C18 column (50 × 2.1 mm, particle size 1.7 µm) using water containing 0.1% formic acid and acetonitrile as mobile phase with optimized gradient elution. Mass spectrometric detection was carried out by selective reaction monitoring mode via positive ESI mode with precursor-to-product transitions of m/z 435.3 > 367.1 and m/z 443.1 > 375.2 for olaparib and 2 H8 -olaparib (internal standard). The method was linear over the concentration range 0.1-2000 ng/ml with correlation coefficient >0.9987. The lower limit of quantitation was 0.1 ng/ml. The method showed excellent accuracy and precision, negligible matrix effect and high extraction recovery. The validated method was subsequently utilized to determine the concentration of olaparib in rat plasma and further applied to the pharmacokinetic study of olaparib in rat plasma. Our results demonstrated that olaparib showed gender-dependent pharmacokinetics in rats. Compared with that in males, olaparib showed high plasma exposure, long half-life, low clearance and high bioavailability in females.

Phase I study of intermittent olaparib capsule or tablet dosing in combination with carboplatin and paclitaxel (part 2).

Background In the first part of this extensive phase I study (NCT00516724), continuous olaparib twice daily (bid) with carboplatin and/or paclitaxel resulted in myelosuppression and dose modifications. Here, we report the safety, tolerability, and efficacy of intermittent olaparib dosing combined with carboplatin and paclitaxel. Methods Patients with advanced solid tumors (part D) and enriched for ovarian and breast cancer (part E) received olaparib (capsule and tablet formulations) using intermittent schedules (2 to 10 days of a 21-day cycle) combined with carboplatin/paclitaxel. Safety assessments included evaluation of dose-limiting toxicities (DLTs; cycle 1 only), adverse events (AEs), and physical examinations. Pharmacokinetic assessments of olaparib capsule and tablet combined with carboplatin/paclitaxel were performed. Tumor responses (RECIST) were assessed every 2 cycles. Results In total, 132 heavily pre-treated patients were included. One DLT of grade 3 elevated alanine aminotransferase lasting for 8 days was reported (olaparib tablet 100 mg bid days 3-12, carboplatin area under the curve 4 and paclitaxel 175 mg/m2). The most common hematological AEs were neutropenia (47%) and thrombocytopenia (39%), which frequently led to dose modifications. Non-hematological AEs were predominantly grade 1-2, including alopecia (89%) and fatigue (84%). Overall objective response rate was 46%. Conclusions Discontinuous dosing of olaparib resulted in significant myelosuppression leading to dose interruptions and/or delays. Anti-tumor activity was encouraging in patients enriched with BRCA-mutated breast and ovarian cancer. The most appropriate olaparib tablet dose for use in further studies evaluating olaparib in combination with carboplatin and paclitaxel is 50 mg bid (days 1-5).

Population Pharmacokinetics of Talazoparib in Patients With Advanced Cancer.

Poly(ADP-ribose) polymerase (PARP) inhibitors have been developed to treat cancers associated with somatic BRCA mutations and germline genetic aberrations involved in the DNA damage response. The efficacy, tolerability, and pharmacokinetic/pharmacodynamic (PK/PD) profile of talazoparib, a potent small-molecule PARP inhibitor, was established in 4 clinical studies in cancer patients (2 phase 1 studies PRP-001 and PRP-002, the phase 2 ABRAZO trial, and the phase 3 EMBRACA trial). The current study aimed to describe the population PK of talazoparib and identify covariates that affect talazoparib PK in patients with advanced cancers using pooled data from these 4 studies. Talazoparib PK was well characterized by a 2-compartment model with first-order absorption and absorption lag time. Based on covariate analysis, no dose adjustment for talazoparib is required based on a patient's age, sex, baseline body weight, Asian race, the presence of mild renal or hepatic impairment, or use of acid-reducing agents. A reduced 0.75-mg daily dose is recommended for patients taking a potent P-glycoprotein inhibitor and those with moderate renal impairment. Insufficient data were available to establish dosing recommendations for patients with severe renal and moderate or severe hepatic impairment. The PK of a single 1-mg talazoparib capsule is comparable with 4 0.25-mg capsules. Talazoparib can be taken with or without food. These data provide support for dosing recommendations and labeling information for talazoparib.

UPLC-MS/MS method for the determination of talazoparib in rat plasma and its pharmacokinetic study.

In the present study, an accurate and sensitive ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the determination of plasma talazoparib concentration in rats was developed and established. The purpose of chromatographic separation of talazoparib and the internal standard (bosutinib) was achieved on an Acquity BEH C18 (2.1 mm × 50 mm, 1.7 µm) column with a flow rate of 0.40 mL/min, using a gradient elution with acetonitrile and 0.1% formic acid in water as the mobile phase. The detection was performed on a XEVO TQ-S triple quadrupole tandem mass spectrometer coupled with electrospray ionization interface under positive-ion multiple reaction monitoring (MRM) mode with the precursor-to-product ion transitions of m/z 381.3 → 285.2 for talazoparib and m/z 530.2 → 141.2 for bosutinib (IS), respectively. The method was linear over the range of 0.5-200 ng/mL for talazoparib. The accuracies and precisions of intra- and inter-day were all within the acceptance limits, and no matrix effect was observed in this method. The validated method was further employed to a pharmacokinetic study of talazoparib after oral treatment with 0.2 mg/kg talazoparib to rats.

Phase I study of continuous olaparib capsule dosing in combination with carboplatin and/or paclitaxel (Part 1).

Background The PARP inhibitor olaparib has shown acceptable toxicity at doses of up to 400 mg twice daily (bid; capsule formulation) with encouraging signs of antitumor activity. Based on its mode of action, olaparib may sensitize tumor cells to DNA-damaging agents. This Phase I trial (NCT00516724) evaluated the safety, pharmacokinetics (PK) and preliminary efficacy of olaparib combined with carboplatin and/or paclitaxel. Methods Patients with advanced solid tumors received olaparib (capsule bid) plus carboplatin (Part A), carboplatin and paclitaxel (Part B), or paclitaxel (Part C). In each part of the study, different drug doses were given to define the most appropriate dose/drug combination to use in further studies. Safety assessments included evaluation of dose-limiting toxicities (DLTs; cycle 1 only), adverse events (AEs) and physical examinations. PK assessments of olaparib, carboplatin and paclitaxel were performed. Tumor responses (RECIST) were assessed every two cycles. Results Fifty-seven patients received treatment. DLTs were reported in two patients (both receiving olaparib 100 mg bid and carboplatin AUC 4; Part A, cohort 2): grade 1 thrombocytopenia with grade 2 neutropenia lasting for 16 days, and grade 2 neutropenia lasting for 7 days. Non-hematologic AEs were predominantly grade 1-2 and included fatigue (70%) and nausea (40%). Bone marrow suppression, mainly neutropenia (51%) and thrombocytopenia (25%), frequently led to dose modifications. Conclusions Olaparib in combination with carboplatin and/or paclitaxel resulted in increased hematologic toxicities, making it challenging to establish a dosing regimen that could be tolerated for multiple cycles without dose modifications.

Preparation and Comparison of Oral Bioavailability for Different Nano-formulations of Olaparib.

Olaparib (OLA) is a poly ADP ribose polymerase (PARP) inhibitor approved for germline BRCA-mutated (gBRCAm) advanced ovarian cancer and breast cancer. Low oral bioavailability of this drug requires increase in the dose and frequency causing haematological toxicity in the patients. The purpose of this study is to prepare different nano-formulations of OLA lipospheres (LP) by melt dispersion and nano-suspensions (NSP) by solvent evaporation (SE) and wet milling (WM) techniques and compare oral bioavailability of these formulations. Size of the nano-formulations OLA-LP, OLA-NSPSE and OLA-NSPWM were found to be 126.71 ± 4.54, 128.6 ± 2.34 and 531.1 ± 5.34 nm with polydispersity index below 0.3. In vitro release studies were performed by dialysis bag method where the sustained drug release was observed from nano-formulations until 9 h with Higuchi for OLA suspended in 2.5% w/v sodium carboxy methyl cellulose (OLA-SP), OLA-LP and OLA-NSPWM and Peppas for OLA-NSPSE-based drug release kinetics. In vivo pharmacokinetic studies, haematological toxicity and distribution studies were performed on rats. Results showed that there was an improvement in Cmax, AUCtotal, t1/2 and MRT by OLA nano-formulations when compared with OLA-SP. OLA-SP has shown reduction in WBC, platelets and lymphocytes at 12 and 36 h time points; however, no reduction in cell count was observed with OLA nano-formulations. Distribution studies proved FITC nano-formulations were most rapidly absorbed and distributed when compared with FITC-loaded suspension. From the above results, it was concluded that OLA nano-formulations can be an alternative to enhance the oral bioavailability and to reduce the haematological toxicity of OLA.

A phase I study of the PD-L1 inhibitor, durvalumab, in combination with a PARP inhibitor, olaparib, and a VEGFR1-3 inhibitor, cediranib, in recurrent women's cancers with biomarker analyses.

BACKGROUND: Strategies to improve activity of immune checkpoint inhibitors are needed. We hypothesized enhanced DNA damage by olaparib, a PARP inhibitor, and reduced VEGF signaling by cediranib, a VEGFR1-3 inhibitor, would complement anti-tumor activity of durvalumab, a PD-L1 inhibitor, and the 3-drug combination would be tolerable. METHODS: This phase 1 study tested the 3-drug combination in a 3 + 3 dose escalation. Cediranib was taken intermittently (5 days on/2 days off) at 15 or 20 mg (dose levels 1 and 2, respectively) with durvalumab 1500 mg IV every 4 weeks, and olaparib tablets 300 mg twice daily. The primary end point was the recommended phase 2 dose (RP2D). Response rate, pharmacokinetic (PK), and correlative analyses were secondary endpoints. RESULTS: Nine patients (7 ovarian/1 endometrial/1 triple negative breast cancers, median 3 prior therapies [2-6]) were treated. Grade 3/4 adverse events include hypertension (1/9), anemia (1/9) and lymphopenia (3/9). No patients experienced dose limiting toxicities. The RP2D is cediranib, 20 mg (5 days on/2 days off) with full doses of durvalumab and olaparib. Four patients had partial responses (44%) and 3 had stable disease lasting ≥6 months, yielding a 67% clinical benefit rate. No significant effects on olaparib or cediranib PK parameters from the presence of durvalumab, or the co-administration of cediranib or olaparib were identified. Tumoral PD-L1 expression correlated with clinical benefit but cytokines and peripheral immune subsets did not. CONCLUSIONS: The RP2D is tolerable and has preliminary activity in recurrent women's cancers. A phase 2 expansion study is now enrolling for recurrent ovarian cancer patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02484404. Registered June 29, 2015.

Pharmacokinetics and safety of olaparib tablets as monotherapy and in combination with paclitaxel: results of a Phase I study in Chinese patients with advanced solid tumours.

PURPOSE: Chinese patients have been enrolled in multiple Phase III trials of the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza); however, the pharmacokinetic (PK) profile of olaparib has not been investigated in this population. This two-part, open-label Phase I study was, therefore, carried out to determine the PK and safety profile of olaparib (tablet formulation) in Chinese patients with advanced solid tumours as monotherapy and in combination with paclitaxel (NCT02430311). METHODS: The PK profile of olaparib 300 mg (twice daily [bid]; Cohort 1) as monotherapy after a single dose and at steady state, and 100 mg (bid; Cohort 2) as monotherapy (single dose and at steady state) and in combination (at steady state) with weekly paclitaxel (80 mg/m2) was assessed during Part A. Patients could continue to receive treatment (monotherapy, Cohort 1; combination therapy, Cohort 2) in Part B, which assessed safety and tolerability. RESULTS: Twenty and 16 patients were enrolled into Cohorts 1 and 2, respectively. Steady-state olaparib exposure increased slightly less than proportionally with increasing monotherapy dose and inter-patient variability was high. A statistically significant decrease in olaparib exposure was seen when given in combination with paclitaxel. Discontinuation due to adverse events (AEs) was rare and haematological AEs were more common in patients receiving combination treatment. CONCLUSIONS: The PK and safety profile of olaparib monotherapy in Chinese patients is consistent with that seen previously in Western and Japanese patients, and the recommended Phase III monotherapy tablet dose (300 mg bid) is suitable for use in this population.