Dataset Information

Tumour cell retention of rucaparib, sustained PARP inhibition and efficacy of weekly as well as daily schedules.

ABSTRACT:

Background

Poly(ADP-ribose) polymerase-1 (PARP) inhibitors (PARPi) exploit tumour-specific defects in homologous recombination DNA repair and continuous dosing is most efficacious. Early clinical trial data with rucaparib suggested that it caused sustained PARP inhibition. Here we investigate the mechanism of this durable inhibition and potential exploitation.

Methods

Uptake and retention of rucaparib and persistence of PARP inhibition were determined by radiochemical and immunological assays in human cancer cell lines. The pharmacokinetics and pharmacodynamics of rucaparib were determined in tumour-bearing mice and the efficacy of different schedules of rucaparib was determined in mice bearing homologous recombination DNA repair-defective tumours.

Results

Rucaparib accumulation is carrier mediated (Km=8.4±1.2??M, Vmax=469±22?pmol per 10(6) cells per 10?min), reaching steady-state levels >10 times higher than the extracellular concentration within 30?min. Rucaparib is retained in cells and inhibits PARP ?50% for ?72?h days after a 30-min pulse of 400?nM. In Capan-1 tumour-bearing mice rucaparib accumulated and was retained in the tumours, and PARP was inhibited for 7 days following a single dose of 10?mg?kg(-1) i.p or 150?mg?kg(-1) p.o. by 70% and 90%, respectively. Weekly dosing of 150?mg?kg(-1) p.o once a week was as effective as 10?mg?kg(-1) i.p daily for five days every week for 6 weeks in delaying Capan-1 tumour growth.

Conclusions

Rucaparib accumulates and is retained in tumour cells and inhibits PARP for long periods such that weekly schedules have equivalent anticancer activity to daily dosing in a pre-clinical model, suggesting that clinical evaluation of alternative schedules of rucaparib should be considered.

SUBMITTER: Murray J

PROVIDER: S-EPMC3992512 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Publications

Tumour cell retention of rucaparib, sustained PARP inhibition and efficacy of weekly as well as daily schedules.

Murray J J Thomas H H Berry P P Kyle S S Patterson M M Jones C C Los G G Hostomsky Z Z Plummer E R ER Boddy A V AV Curtin N J NJ

British journal of cancer 20140220 8

<h4>Background</h4>Poly(ADP-ribose) polymerase-1 (PARP) inhibitors (PARPi) exploit tumour-specific defects in homologous recombination DNA repair and continuous dosing is most efficacious. Early clinical trial data with rucaparib suggested that it caused sustained PARP inhibition. Here we investigate the mechanism of this durable inhibition and potential exploitation.<h4>Methods</h4>Uptake and retention of rucaparib and persistence of PARP inhibition were determined by radiochemical and immunolo ...[more]

PMID: 24556618

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Project description:Abstract Somapacitan is a long-acting, reversible albumin-binding human growth hormone (GH) derivative based on a proven protraction technology. The objective of this trial was to evaluate the safety, efficacy and treatment satisfaction of once-weekly somapacitan compared with daily GH (Norditropin®) over 52 weeks in Japanese patients with adult GH deficiency (AGHD). This was a phase 3, multicenter, randomized, open-label, parallel-group, active-controlled trial (NCT03075644). Patients previously treated with human GH were randomized 1:3 to either daily GH or somapacitan, respectively, to undergo 20 weeks of dose titration and 32 weeks of fixed-dose treatment. The primary endpoint was the incidence of adverse events (AEs) from baseline to week 53. Secondary endpoints included change from baseline in visceral, subcutaneous and total adipose tissue (VAT, SAT and TAT, respectively) assessed with computerized tomography scans; change from baseline in treatment satisfaction evaluated using Treatment Satisfaction Questionnaire for Medication (TSQM-9) scores; and occurrence of anti-somapacitan antibodies. In total, 62 patients were randomized (16 to the daily GH and 46 to the somapacitan treatment arm), of which 60 completed the trial. Baseline characteristics for daily GH vs somapacitan groups, respectively, were: 43.8% vs 47.8% female, 87.5% vs 80.4% adult-onset GH deficiency, mean (SD) age 49.3 (11.5) vs 54.1 (12.1) years, weight 67.9 (12.0) vs 69.4 (22.7) kg, body mass index 24.8 (3.7) vs 26.4 (6.7) kg/m2, and GH dose at screening 0.29 (0.14) vs 0.31 (0.17) mg. Rate of AEs per 100 patient-years was similar between treatment arms (309.8 for daily GH, 312.7 for once-weekly somapacitan); most AEs were mild (97.9% and 93.1%, respectively) and none were severe. Four AEs in the somapacitan arm were serious; all were considered unlikely related to treatment. No anti-somapacitan antibodies were detected during treatment. Mean insulin-like growth factor-I standard deviation score (IGF-I SDS) at baseline was maintained with both treatments. The majority of the patients had IGF-I SDS values below +2. No significant differences in VAT, SAT and TAT were seen in both treatment groups after 52 weeks (estimated difference, somapacitan – daily GH [95% CI]): –1.74 [–18.13; 14.66], –11.53 [–35.54; 12.48], and –12.85 [–47.31; 21.62] cm2, respectively. TSQM-9 scores were not significantly different between treatments, but showed a tendency in favor of somapacitan (estimated difference [95% CI]): 4.87 [–3.46; 13.20] for effectiveness, 6.79 [–1.04; 14.61] for convenience, and 6.88 [–1.08; 14.85] for overall satisfaction. No new safety concerns were identified. Improvements in body composition were similar in the GH and somapacitan cohorts. The safety and tolerability of somapacitan in Japanese patients with AGHD were consistent with results from the global phase 3 trial (REAL 1).

Dataset Information

Tumour cell retention of rucaparib, sustained PARP inhibition and efficacy of weekly as well as daily schedules.

Background

Methods

Results

Conclusions

Publications

Tumour cell retention of rucaparib, sustained PARP inhibition and efficacy of weekly as well as daily schedules.

Similar Datasets

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