Results from a Phase 1b/2 Study of Ibrutinib Combination Therapy in Advanced Urothelial Carcinoma.

Ibrutinib is a first-in-class Bruton's tyrosine kinase inhibitor approved for the treatment of various B-cell malignancies and chronic graft-versus-host disease. We evaluated the safety and efficacy of ibrutinib, alone or combined with standard-of-care regimens, in adults with advanced urothelial carcinoma (UC). Once-daily ibrutinib was administered orally at 840 mg (single-agent or with paclitaxel) or at 560 mg (with pembrolizumab). Phase 1b determined the recommended phase 2 dose (RP2D) of ibrutinib, and phase 2 assessed progression-free survival (PFS), overall response rate (ORR), and safety. Thirty-five, eighteen, and fifty-nine patients received ibrutinib, ibrutinib plus pembrolizumab, and ibrutinib plus paclitaxel at the RP2D, respectively. Safety profiles were consistent with those of the individual agents. The best-confirmed ORRs were 7% (two partial responses) with single-agent ibrutinib and 36% (five partial responses) with ibrutinib plus pembrolizumab. Median PFS was 4.1 months (range, 1.0-37.4+) with ibrutinib plus paclitaxel. The best-confirmed ORR was 26% (two complete responses). In previously treated patients with UC, ORR was higher with ibrutinib plus pembrolizumab than with either agent alone (historical data in the intent-to-treat population). ORR with ibrutinib plus paclitaxel was greater than historical values for single-agent paclitaxel or ibrutinib. These data warrant further evaluation of ibrutinib combinations in UC.

Phase I study of anti-epidermal growth factor receptor antibody-drug conjugate serclutamab talirine: Safety, pharmacokinetics, and antitumor activity in advanced glioblastoma.

Background: Serclutamab talirine (Ser-T, formerly ABBV-321) is an antibody-drug conjugate consisting of an antibody (AM-1-ABT-806) directed against activated epidermal growth factor receptor (EGFR) and a pyrrolobenzodiazepine dimer. We investigated Ser-T monotherapy in a phase I, first-in-human, dose-escalation, and dose-expansion study in patients with advanced solid tumors associated with EGFR overexpression. Methods: Eligible patients (≥18 years) had advanced, histologically confirmed solid tumors associated with EGFR overexpression (centralized testing). Patients received Ser-T intravenously once every 4 weeks (Q4W; 5-50 µg/kg) in the dose-escalation phase. Herein, preliminary antitumor activity at the recommended phase II dose (RP2D) is reported only for patients with glioblastoma (n = 24); additional assessments included all treated patients. Results: Sixty-two patients (median age: 58 years) were enrolled within the dose-escalation (n = 43) and dose-expansion (n = 19) phases. One dose-limiting toxicity, grade 3 aspartate aminotransferase and alanine aminotransferase elevation, occurred at 20 µg/kg during dose escalation. The Ser-T RP2D regimen of 50 µg/kg × 1 (loading dose) followed by 25 µg/kg Q4W (maintenance dose) was administered during dose expansion. Fatigue (37%) was the only treatment-emergent adverse event (AE) occurring in >25% of patients. Two patients (3%) reported mild treatment-related ocular AEs (eye pruritus). Responses in patients with glioblastoma included 1 partial response (~33 months), 6 stable disease, and 14 progressive disease (not evaluable: n = 3). Conclusions: Ser-T monotherapy at doses up to 50 µg/kg initial dose, followed by 25 µg/kg Q4W demonstrated a tolerable safety profile with minimal antitumor activity observed in patients with glioblastoma. The glioblastoma dose-expansion cohort was closed due to a lack of efficacy (NCT03234712).

Population Pharmacokinetic and Exposure-Safety Analyses of Ibrutinib for the Treatment of Chronic Graft-Versus-Host Disease.

The population pharmacokinetic (PK) and exposure-response (E-R) analyses for the safety of ibrutinib for the treatment of chronic graft-versus-host disease (cGVHD) is presented. This work aims to develop a population PK model for ibrutinib based on data from clinical studies in subjects with cGVHD, to evaluate the impact of intrinsic and extrinsic factors on PK parameters as well as systemic exposure levels, and to assess an E-R relationship for selected safety end points. Pooled data from 162 subjects with cGVHD enrolled in 4 clinical studies were included in the population PK analysis. In the studies, an ibrutinib dose of 420 mg once daily was administered orally. With the exception of 1 study, the study protocols instructed for a reduction of the ibrutinib dose to 140 or 280 mg once daily, depending on concomitant CYP3A inhibitor use. Concomitant CYP3A inhibitor use was found to be a primary covariate for relative bioavailability (F1): the F1 value increased 2.22-fold with concomitant moderate CYP3A inhibitors and 3.09-fold with concomitant strong CYP3A inhibitors, compared with the F1 value in the absence of CYP3A inhibitors. In addition, Japanese ethnicity led to an F1 value that was 1.70-fold higher than that in the non-Japanese population. Simulations using the final PK model suggest that ibrutinib exposure was appropriately controlled within the therapeutic range in the entire cGVHD population by applying dose reductions depending on the use of CYP3A inhibitors, and that additional dose modification for the Japanese population would not be required. The subsequent E-R analysis suggests no apparent association between the systemic exposure to ibrutinib and the selected safety end points.

A randomized, double-blind, placebo-controlled, dose-response study to assess the pharmacokinetics, efficacy, and safety of gabapentin enacarbil in subjects with restless legs syndrome.

OBJECTIVE: The objective of this study was to determine steady-state gabapentin exposures and corresponding relief of symptoms and safety profile produced by 4 dose levels of gabapentin enacarbil (GEn) in subjects with restless legs syndrome (RLS). METHODS: Subjects with RLS (n = 217) were randomized to receive once-daily, orally administered GEn 600 (n = 48), 1200 (n = 45), 1800 (n = 38), or 2400 mg (n = 45) or placebo (n = 41) in this 12-week, double-blind, multicenter study (NCT01332305). Clinic visits were at screening, baseline, and weeks 1, 2, 3, 4, 6, 8, 10, and 12; plasma gabapentin concentrations were measured by a validated liquid chromatography-mass spectrometry/mass spectrometry method at weeks 4 and 12. RESULTS: Exposure to gabapentin was proportional to GEn dose. Time to maximum plasma concentration was 7 to 9 hours, and elimination half-life was ~6 hours. The mean reduction from baseline to week 12 in International Restless Legs Syndrome Rating Scale total score and proportions of subjects with "much improved"/"very much improved" Clinical Global Impression-Improvement scores (investigator and patient ratings) ranged from -12.9 to -13.9 for GEn treatment groups versus -9.3 for placebo. The 2 most commonly reported adverse events were somnolence and dizziness. CONCLUSIONS: Gabapentin exposure was approximately proportional to GEn dose. Efficacy data showed that a once-daily dose of GEn 600 to 2400 mg provides greater relief of RLS symptoms than placebo; GEn was generally well tolerated with an adverse event profile consistent with gabapentin.

Evaluation of gabapentin enacarbil on cardiac repolarization: a randomized, double-blind, placebo- and active-controlled, crossover thorough QT/QTc study in healthy adults.

BACKGROUND: Gabapentin enacarbil, a transported prodrug of gabapentin, was recently approved by the US Food and Drug Administration for the treatment of moderate to severe restless legs syndrome. OBJECTIVE: As part of the overall safety evaluation of gabapentin enacarbil, the present definitive QT/QTc study was conducted to assess the effects of gabapentin enacarbil on cardiac repolarization in accordance with the International Conference on Harmonization E14 guidance. METHODS: This randomized, double-blind, placebo- and active-controlled, crossover study enrolled 54 healthy adults. Subjects were randomly assigned to receive a single oral dose of gabapentin enacarbil 1200, 6000 mg, moxifloxacin 400 mg (active control), and placebo in a randomized sequence, with treatment periods separated by a 7-day washout. Blood samples were collected for pharmacokinetic analysis, and continuous ECG measurements were recorded using a Holter monitor. The primary end point was the time-matched difference in individualized baseline-adjusted QTc (ddQTcIb) between gabapentin enacarbil and placebo. General tolerability was also monitored. RESULTS: Of the 54 subjects enrolled in the study (mean [SD] age, 29.2 [10.1]; 42.6% female; mean body mass index, 25.8 [3.0]), 48 (88.9%) completed the study, and 6 were discontinued prematurely after having received ≥ 1 dose of study medication. Thus, the numbers of patients in the safety population were: gabapentin enacarbil 1200 mg, 50; gabapentin enacarbil 6000 mg, 50; moxifloxacin, 50; and placebo, 51. The maximum ddQTcIb values were 0.7 msec (upper 95% confidence limit [CL], 3.0) with gabapentin enacarbil 1200 mg; 1.3 msec (upper CL, 3.6) with gabapentin enacarbil 6000 mg; and 7.4 msec (lower CL, 5.1) with moxifloxacin. A QT-concentration relationship was reported with moxifloxacin. Gabapentin exposures were dose-proportional with gabapentin enacarbil doses of 1200 and 6000 mg. The most commonly reported adverse events with gabapentin enacarbil 6000 mg were dizziness and somnolence (60.0% and 54.0%, respectively). CONCLUSION: In this population of healthy adults, gabapentin enacarbil at doses of 1200 and 6000 mg was not associated with QT prolongation and was generally well-tolerated.

Functional activity of a large neutral amino acid transporter (LAT) in rabbit retina: a study involving the in vivo retinal uptake and vitreal pharmacokinetics of L-phenyl alanine.

PURPOSE: The purpose of this study is to elucidate the functional activity of large neutral amino acid transporter (LAT) in rabbit retina and to delineate its role in the retinal uptake and intravitreal pharmacokinetics of L-phenylalanine (L-Phe). METHODS: In vivo retinal uptake of L-Phe and L-alanine (L-Ala) was determined in the presence and absence of specific transport inhibitors following intravitreal administration. L and D isomers of amino acids were employed as inhibitors to determine the stereo-selectivity of LAT. Reverse transcription-polymerase chain reaction (RT-PCR) was carried out for LAT isoforms (LAT1 and LAT2). Vitreal disposition of L-Phe following administration in rabbit vitreous was studied in the presence of an other competing LAT substrate D-methionine using microdialysis. RESULTS: Retinal uptake of L-Phe was significantly inhibited in presence of a specific LAT inhibitor, 2-aminobicyclo-[2,2,1]-heptane-2-carboxylic acid (BCH), L isomers of large neutral amino acids and LAT1 specific but not by LAT2 specific and charged amino acids. No significant inhibition of L-Ala retinal uptake was observed with LAT substrates. LAT isoforms (LAT1 and LAT2) were identified by RT-PCR in rabbit retina. The mean residence time (MRT) and area under curve (AUC) values of L-Phe following intravitreal administration were significantly increased in the presence of D-methionine, a LAT substrate. CONCLUSIONS: This study demonstrates the functional activity and molecular expression of large neutral amino acid transporter in the rabbit retina. Furthermore, based on these studies it can be concluded that LAT is involved in the retinal uptake and intravitreal elimination of L-Phe.

Validation of an ocular microdialysis technique in rabbits with permanently implanted vitreous probes: systemic and intravitreal pharmacokinetics of fluorescein.

The purpose of this work is to validate a novel ocular microdialysis sampling technique in rabbits with permanently implanted vitreous probes. This objective is achieved by studying the vitreous pharmacokinetics of fluorescein following systemic and intravitreal administration. The rabbits were divided into two groups (groups I and II) based on whether or not they were allowed a recovery period following surgical implantation of probes. The integrity of the blood-retinal barrier was determined by the vitreal protein concentrations and the fluorescein permeability index. Vitreal protein concentrations returned to baseline 48 h after probe implantation and therefore experiments were conducted 72 h post-implantation of probes in rabbits where recovery period was allowed. The permeability indices for fluorescein after systemic administration in group I (without recovery period) and group II (with recovery period) indicated that the integrity of the blood-retinal barrier was maintained and were found out to be 0.55 +/- 0.27 and 0.71 +/- 0.38%, respectively, for the vitreous chamber. Following microdialysis probe implantation in the group II rabbits, the blood-retinal barrier integrity was not compromised. A novel microdialysis technique in rabbits with permanently implanted probes for studying the pharmacokinetics of posterior segment has been developed and characterized.

Mechanism of a model dipeptide transport across blood-ocular barriers following systemic administration.

The purposes of this study were to provide functional evidence for the presence of a peptide transporter on blood-ocular barriers and to elucidate the mechanism of a dipeptide transport across these barriers following systemic administration. Glycylsarcosine was chosen as a model dipeptide and [(3)H] glycylsarcosine was administered through the marginal ear vein of New Zealand white rabbits. At the end of an experimental period, vitreous humor, retina and aqueous humor were collected. Time dependent uptake of glycylsarcosine into ocular tissues was studied at 5, 10, 15 and 30 min. Competitive inhibition studies were performed by intravenous administration of [(3)H] glycylsarcosine with and without various inhibitors. Concentration-dependent ocular uptake of glycylsarcosine was carried out by administration of various concentrations of unlabelled glycylsarcosine spiked with a fixed amount of [(3)H] glycylsarcosine. Time-dependent uptake of glycylsarcosine into vitreous humor, retina and aqueous humor for a period of 30 min following systemic administration was linear. Ocular uptake of glycylsarcosine was inhibited by peptide transporter substrates such as dipeptides (glycylproline and carnosine) and captopril but not by non-substrates such as amino acids. Concentration-dependent self-inhibition of glycylsarcosine ocular uptake was also observed. The results indicate that model dipeptide is transported across blood-ocular barriers via a carrier-mediated process. In conclusion, an oligopeptide transport system is involved in the transport of glycylsarcosine across blood-ocular barriers. This information may be utilized to design transporter/receptor targeted drug delivery systems for efficient ocular uptake from systemic administration.

Disposition of short-chain aliphatic alcohols in rabbit vitreous by ocular microdialysis.

Anatomic and physiological barriers limit drug delivery to the posterior segment of the eye via topical or systemic administration. Intravitreal administration has proven to be a safe and effective means of treating various posterior segment diseases. Elimination of a compound from the vitreous chamber may depend on lipophilicity, diffusivity, and aqueous solubility. This information is critical for optimizing intravitreal dosing which in turn can aid in the design of drug delivery systems. The purpose of this study is to determine the vitreous disposition of an ascending homologous series of short chain aliphatic alcohols ranging from hydrophilic methanol to lipophilic 1-heptanol by microdialysis. Radiolabelled 14C-methanol, 14C-1-propanol, 14C-1-pentanol, and 14C-1-heptanol with log partition coefficient values ranging from -0.77 to 2.7 were studied. Microdialysis probes were implanted in both anterior and vitreous chamber of the rabbit eye to sample aqueous and vitreous humors simultaneously. Concentric probe was implanted in vitreous chamber about 3mm below the cornealscleral limbus. Linear probe was implanted in the anterior chamber using a 25-guage needle. Isotonic phosphate buffer saline (IPBS) (pH 7.4) was perfused through the probe with a flow rate of 2 microlml(-1). Alcohols (2.0 microg-130.72 microg) were injected into the vitreous body. In vitro recovery for the probes was calculated using respective alcohols in IPBS. Pharmacokinetic parameters were determined by non-compartmental analysis. Vitreal elimination half-lives of methanol, 1-propanol, 1-pentanol and 1-heptanol are 52.0+/-5.7, 58.5+/-5.8, 72.9+/-5.8 and 153.7+/-21.6 min, respectively. Dose normalized area under the aqueous concentration time curve values of methanol, 1-propanol and 1-pentanol are 33.8+/-13.4, 28.3+/-11.9 and 29.2+/-4.9 microgminml(-1)microg(-1)10(-2), respectively. Time taken to reach maximum concentration in the anterior chamber for methanol, 1-propanol and 1-pentanol is 120+/-42, 160+/-26, and 260+/-26 min, respectively. The maximum concentration of methanol, 1-propanol and 1-pentanol achieved in the anterior chamber is 18.6+/-10.3, 9.4+/-3.2, and 5.9+/-1.3 microgml(-1)10(-4) respectively. Detectable 1-heptanol levels were not observed in the anterior chamber with the intravitreal dose administered. The shorter vitreal elimination half-lives of the alcohols studied suggest retina as major route of elimination from the vitreous body. The elimination rate constants of alcohols from the vitreous appear to be progressively decreasing with ascending chain length and lipophilicity (methanol to 1-heptanol). Among the alcohols studied, methanol produced the highest concentration in the anterior chamber following vitreal administration.

Ocular penetration of acyclovir and its peptide prodrugs valacyclovir and val-valacyclovir following systemic administration in rabbits: An evaluation using ocular microdialysis and LC-MS.

PURPOSE: To investigate the ocular penetration of acyclovir and its prodrugs following systemic administration and to elucidate the mechanism of penetration. METHODS: Hydrophilic peptide prodrugs of acyclovir were infused intravenously in New Zealand albino rabbits over 45 min at a dose equivalent to 30 mmoles/kg acyclovir. Aqueous and vitreous humor samples were obtained utilizing ocular microdialysis and blood samples were obtained from the mid ear vein using a cannula. RESULTS: The plasma bioavailability for acyclovir, valacyclovir and val-valacyclovir were similar with area under curve values being 896.24 (+/-143.58), 776.54 (+/-197.52), 824.69 (+/-217.43) min x micromoles/L respectively. Anterior segment area under curve values were 53.70 (+/-35.58), 139.85 (+/-9.43) and 291.05 (+/-88.13) min x micromoles/L respectively while the mean residence time values were 46.47 (+/-24.94), 76.30 (+/-7.24) and 188.39 (+/-80.73) min respectively. Vitreous levels of the prodrugs were not measurable. CONCLUSIONS: The valine and valine-valine ester prodrugs of ACV penetrated the anterior segment of the eye much better than acyclovir alone, probably via a carrier mediated transport mechanism.