Multidrug regimens and corresponding drug interactions cause many adverse reactions and treatment failures. Drug efflux transporters: P-gp, MRP, BCRP in conjunction with metabolizing enzymes (CYPs) are major factors in such interactions. Most effective combination antiretrovirals (ARV) therapy includes a PI or a NNRTI or two NRTI. Coadministration of such ARV may induce efflux transporters and/or CYP3A4 resulting in sub-therapeutic blood levels and therapeutic failure due to reduced absorption and/or increased metabolism. A similar prognosis is true for ARV-compounds and drugs of abuse combinations. Morphine and nicotine enhance CYP3A4 and MDR1 expression in vitro. A 2.5 fold rise of cortisol metabolite was evident in smokers relative to nonsmokers. Altered functions of efflux transporters and CYPs in response to ARV and drugs of abuse may result in altered drug absorption and metabolism. Appropriate in vitro models can be employed to predict such interactions. Influence of genetic polymorphism, SNP and inter-individual variation in drug response has been discussed. Complexity underlying the relationship between efflux transporters and CYP makes it difficult to predict the outcome of HAART as such, particularly when HIV patients taking drugs of abuse do not adhere to HAART regimens. HIV+ pregnant women on HAART medications, indulging in drugs of abuse, may develop higher viral load due to such interactions and lead to increase in mother to child transmission of HIV. A multidisciplinary approach with clear understanding of mechanism of interactions may allow proper selection of regimens so that desired therapeutic outcome of HAART can be reached without any side effects.

Boehringer Ingelheim.

The objectives of this study were (i) to characterize the interaction of vandetanib with P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp1) in vitro and in vivo (ii) to study the modulation of P-gp and BCRP mediated efflux of vandetanib with specific transport inhibitors and m-TOR inhibitors, everolimus and temsirolimus. Cellular accumulation and bi-directional transport studies in MDCKII cell monolayers were conducted to delineate the role of efflux transporters on disposition of vandetanib. Brain distribution studies were conducted in male FVB wild-type mice with vandetanib administered intravenously either alone or in the presence of specific inhibitors and m-TOR inhibitors. In vitro studies suggested that vandetanib is a high affinity substrate of Bcrp1 but is not transported by P-gp. Interestingly, in vivo brain distribution studies in FVB wild type mice indicated that vandetanib penetration into the brain is restricted by both Bcrp1 and P-gp mediated active efflux at the blood brain barrier (BBB). Co-administration of elacridar, a dual P-gp/BCRP inhibitor increased the brain to plasma concentration ratio of vandetanib upto 5 fold. Of the two m-TOR pathway inhibitors examined; everolimus showed potent effect on modulating vandetanib brain penetration whereas no significant affect on vandetanib brain uptake was observed following temsirolimus co-administration. This finding could be clinically relevant as everolimus can provide synergistic pharmacological effect in addition to primary role of vandetanib efflux modulation at BBB for the treatment of brain tumors.

Background and ObjectiveRisankizumab is an anti-interleukin (IL)-23 monoclonal antibody being developed for treatment of moderate to severe plaque psoriasis. This study provided a comprehensive analysis of risankizumab pharmacokinetics in healthy subjects and patients with plaque psoriasis using data across phase I–III clinical trials.MethodsPlasma pharmacokinetic data from 1899 subjects, including 13,123 observations, who received single or multiple intravenous or subcutaneous doses of risankizumab (0.01–5 mg/kg intravenous [IV], 200–1200 mg IV, 0.25–1 mg/kg subcutaneous [SC], and 18–300 mg SC) across the phase I–III clinical program were analyzed using a non-linear mixed-effects modeling approach. The developed model was qualified and the clinical relevance of covariates statistically correlated with risankizumab clearance (CL) was evaluated using simulation analyses.ResultsRisankizumab pharmacokinetics were best described using a two-compartment model with first-order absorption and elimination. Risankizumab CL, volume of distribution at steady state (Vss), and terminal-phase elimination half-life (t½) were estimated to be approximately 0.31 L/day, 11.2 L, and 28 days, respectively, for a typical 90 kg psoriatic subject, approaching steady-state plasma exposures by week 16 of dosing. Absolute SC bioavailability (F) was 89%. Bodyweight, anti-drug antibody (ADA) titers ≥ 128 (detected in only 1% of ADA-evaluable subjects in phase III studies), baseline serum albumin, high-sensitivity C-reactive protein (hs-CRP), and serum creatinine were statistically correlated with risankizumab CL; however, they had no clinically relevant impact on exposure.ConclusionRisankizumab is characterized by dose-proportional, bi-exponential disposition with no difference in exposure between healthy subjects and patients with psoriasis. None of the covariates identified as being statistically correlated with risankizumab CL has a clinically meaningful impact on its exposure with the proposed psoriasis clinical regimen of 150 mg administered SC at weeks 0 and 4, and every 12 weeks thereafter.ClinicalTrials.gov IdentifiersNCT01577550, NCT02054481, NCT02596217, NCT02684370, NCT02672852, NCT02684357, NCT02694523.

Purpose Small cell lung cancer (SCLC) is an aggressive malignancy with limited treatments. Delta-like ligand 3 (DLL3) is aberrantly expressed in most SCLC. Tarlatamab (AMG 757), a bispecific T cell engager molecule, binds both DLL3 and CD3 leading to T cell-mediated tumor lysis. Herein, we report phase 1 results of tarlatamab in patients with SCLC. Patients and Methods This study evaluated tarlatamab in patients with relapsed/refractory SCLC. The primary endpoint was safety. Secondary endpoints included antitumor activity by modified RECIST 1.1, overall survival (OS), and pharmacokinetics. Results By July 19, 2022, 107 patients received tarlatamab in dose exploration (0.003 to 100 mg; n=73) and expansion (100 mg; n=34) cohorts. Median prior lines of anticancer therapy were 2 (range, 1–6); 49.5% received anti-programmed death-1/programmed death ligand-1 therapy. Any grade treatment-related adverse events (TRAEs) occurred in 97 patients (90.7%); grade ≥ 3 in 33 patients (30.8%). One patient (1%) had grade 5 pneumonitis. Cytokine release syndrome was the most common TRAE, occurring in 56 patients (52%) including grade 3 in 1 patient (1%). Maximum tolerated dose was not reached. Objective response rate (ORR) was 23.4% (95% CI: 15.7, 32.5) including 2 complete and 23 partial responses. Median duration of response was 12.3 months (95% CI: 6.6, 14.9). Disease control rate was 51.4% (95% CI: 41.5, 61.2). Median progression-free survival and OS were 3.7 months (95% CI: 2.1, 5.4) and 13.2 months (95% CI: 10.5, to not reached), respectively. Exploratory analysis suggests that selecting for increased DLL3 expression can result in increased clinical benefit. Conclusion In patients with heavily pretreated SCLC, tarlatamab demonstrated manageable safety with encouraging response durability. Further evaluation of this promising molecule is ongoing.