Considerations and recommendations for assessment of plasma protein binding and drug-drug interactions for siRNA therapeutics.

At the time of writing, although siRNA therapeutics are approved for human use, no official regulatory guidance specific to this modality is available. In the absence of guidance, preclinical development for siRNA followed a hybrid of the small molecule and biologics guidance documents. However, siRNA differs significantly from small molecules and protein-based biologics in its physicochemical, absorption, distribution, metabolism and excretion properties, and its mechanism of action. Consequently, certain reports typically included in filing packages for small molecule or biologics may benefit from adaption, or even omission, from an siRNA filing. In this white paper, members of the 'siRNA working group' in the IQ Consortium compile a list of reports included in approved siRNA filing packages and discuss the relevance of two in vitro reports-the plasma protein binding evaluation and the drug-drug interaction risk assessment-to support siRNA regulatory filings. Publicly available siRNA approval packages and the literature were systematically reviewed to examine the role of siRNA plasma protein binding and drug-drug interactions in understanding pharmacokinetic/pharmacodynamic relationships, safety and translation. The findings are summarized into two decision trees to help guide industry decide when in vitro siRNA plasma protein binding and drug-drug interaction studies are warranted.

In Vitro Drug-Drug Interaction Evaluation of GalNAc Conjugated siRNAs Against CYP450 Enzymes and Transporters.

Small interfering RNAs (siRNAs) represent a new class of medicines that are smaller (∼16,000 Da) than biologic therapeutics (>150,000 Da) but much larger than small molecules (<900 Da). Current regulatory guidance on drug-drug interactions (DDIs) from the European Medicines Agency, Food and Drug Administration, and Pharmaceutical and Medical Devices Agency provides no recommendations for oligonucleotide therapeutics including siRNAs; therefore, small molecule guidance documents have historically been applied. Over ∼10 years, in vitro DDI investigations with siRNAs conjugated to a triantennary N-acetylgalactosamine [(GalNAc)-siRNA] ligand have been conducted during nonclinical drug development to elucidate the potential clinical DDI liability. GalNAc siRNAs were evaluated as substrates, inhibitors, or inducers of major cytochrome P450s (P450s) and as substrates and inhibitors of transporters. Aggregate analysis of these data demonstrates a low potential for DDI against P450s. Zero of five, 10, and seven are inducers, time-dependent inhibitors, or substrates, respectively, and nine of 12 do not inhibit any P450 isoform evaluated. Three GalNAc siRNAs inhibited CYP2C8 at supratherapeutic concentrations, and one mildly inhibited CYP2B6. The lowest K i value of 28 µM is >3000-fold above the therapeutic clinical C max at steady state, and importantly no clinical inhibition was projected. Of four GalNAc siRNAs tested none were substrates for transporters and one caused inhibition of P-glycoprotein, calculated not to be clinically relevant. The pharmacological basis for DDIs, including consideration of the target and/or off-target profiles for GalNAc siRNAs, should be made as part of the overall DDI risk assessment. If modulation of the target protein does not interfere with P450s or transporters, then in vitro or clinical investigations into the DDI potential of the GalNAc siRNAs are not warranted. SIGNIFICANCE STATEMENT: Recommendations for evaluating DDI potential of small molecule drugs are well established; however, guidance for novel modalities, particularly oligonucleotide-based therapeutics are lacking. Given the paucity of published data in this field, in vitro DDI investigations are often conducted. The aggregate analysis of GalNAc-siRNA data reviewed herein demonstrates that, like new biological entities, these oligonucleotide-based therapeutic drugs are unlikely to result in DDIs; therefore, it is recommended that the need for in vitro or clinical investigations similarly be determined on a case-by-case basis. Given the mechanism of siRNA action, special consideration should be made in cases where there may be a pharmacological basis for DDIs.

Comparison of Continuous Thoracic Epidural With Erector Spinae Block for Postoperative Analgesia in Adult Living Donor Hepatectomy.

BACKGROUND: Thoracic epidural analgesia (TEA) is commonly used for pain management in donor hepatectomy. Erector spinae plane block (ESPB) is a newer ultrasound-guided block described for the management of thoracic and abdominal pain. There is limited literature available comparing the two techniques. The objective of this study was to compare the postoperative analgesic efficacy and adverse effects of continuous ESPB to continuous TEA in donor hepatectomy. METHODOLOGY: The randomized controlled trial (RCT) was registered on ClinicalTrials.gov (NCT04151511). A total of 82 patients undergoing donor hepatectomy between January 2020 and December 2020 were recruited, of whom 41 received TEA and 41 received ESPB. Randomization was done by the sealed opaque envelope method. RESULTS:  The mean visual analog scale (VAS) scores in donors who received TEA and ESPB in post-anesthesia care unit (PACU) (2.7 + 0.9 vs. 2.4 + 0.5; P = 0.02) at one hour (2.7 + 0.9 vs. 2.2 + 0.6; P = 0.008), six hours (1.8 + 0.9 vs. 0.8 + 0.5; P < 0.001), 12 hours (0.9 + 0.7 vs. 0.2 + 0.7; P < 0.001), and 24 hours (0.48 + 0.5 vs. 0.08 + 0.3; P < 0.001) were significantly different. Mean opioid consumption was 3.38 ± 6.24 mg in the ESPB group and 10.75 ± 9.64 mg in the TEA group (P < 0.001). Mean lung volume (MLV) at 24 hours in the TEA group and ESPB group was 1543 ml and 1815 ml (P < 0.001). MLV was 2545 ml in the TEA group and 2820 ml in the ESPB group at 48 hours (P < 0.001). Mean nausea and vomiting score at six hours was 0.1 vs. 0.03 (P = 0.02). CONCLUSION:  ESPB improves pain control after donor hepatectomy with an enhanced safety profile and reduced opioid consumption.