Estimation of the future remnant liver function is a better tool to predict post-hepatectomy liver failure than platelet-based liver scores.

INTRODUCTION: Recently, there has been increasing interest in the preoperative prediction and prevention of post-hepatectomy liver failure (PHLF). This is a particular concern in colorectal liver metastases (CRLM), when surgery follows potentially hepatotoxic chemotherapy. Platelet-based liver scores (PBLS) such as APRI and FIB-4 are predictive of chemotherapy-associated liver injury (CALI) and PHLF. Estimation of the future liver remnant function (eFLRF) by combining 99mTc-Mebrofenin Hepatobiliary Scintigraphy (HBSBSA) with future liver remnant volume ratio (FLRV%), is predictive of PHLF and related mortality. We hypothesized that a HBSBSA based formula was a better predictor for PHLF than PBLS in chemotherapy-pretreated CRLM. METHODS: Between 2012 and 2016, 140 patients underwent liver resection for CRLM following systemic therapy. HBSBSA, FLRV%, eFLRF and PBLS were calculated and compared for their value in predicting PHLF. RESULTS: eFLRF and FLRV% had a better predictive value for PHLF than HBSBSA alone and APRI and FIB-4 (AUC = 0.800, 0.843 versus 0.652, 0.635 and 0.658 respectively). In a subgroup analysis (Oxaliplatin all, Oxaliplatin ≥ 6 cycles, Irinotecan all and Irinotecan ≥ 6 cycles), eFLRF was the only factor predictive for PHLF in all subgroups (all: p ≤ 0.05). Prediction of HBSBSA for chemotherapy associated steato-hepatitis (CASH) reached almost significance (p = 0.06). FIB-4 was predictive for sinusoidal obstruction syndrome (SOS) (p = 0.011). Only weak correlation was found between HBSBSA and PBLS. CONCLUSION: eFLRF is a better predictor of PHLF than PBLS or HBSBSA alone. PBLS seem to measure other aspects of liver function or damage than HBSBSA.

Predictability of intranasal pharmacokinetics in man using pre-clinical pharmacokinetic data with a dopamine 3 receptor agonist, PF-219061.

(R)-3-(4-propylmorpholin-2-yl) phenol (PF-219061) is a potent, selective agonist of the dopamine 3 receptor for the treatment of female sexual dysfunction. In vivo, PF-219061 exhibits liver blood flow clearance in both rat and dog. Oral bioavailability was 0.7% in dog and less than 5% in rat. Intranasal dosing was investigated to improve bioavailability. Pre-clinical assessments in rat and dog demonstrated intranasal bioavailabilities of 16-38% in rat and 54-61% in dog with very rapid absorption. It was predicted that an intranasal dose in man would give approximately 25-50% bioavailability. The clinical data verified the preclinical predictions demonstrating rapid absorption and approximately dose-proportional increases in exposure. The intranasal bioavailability in man was estimated to be 26-38%. These findings indicate the potential utility of intranasal dosing as a route that circumvents the first-pass effects for PF-219061 resulting in high exposures.