Robert J. Israel

Tolerability, Gut Effects, and Pharmacokinetics of Methylnaltrexone Following Repeated Intravenous Administration in Humans

Previous studies have shown that a single dose of methylnaltrexone, a unique peripheral opioid antagonist, reverses opioid‐induced gut hypomotility in humans. Because repeated drug doses are likely to be needed to treat patients with opioid‐induced or postsurgical bowel dysfunction, the authors have now examined the safety, pharmacological activity, and pharmacokinetics of a multiple‐dose regimen of methylnaltrexone, administered as 12 consecutive intravenous doses (0.3 mg/kg every 6 hours) in 12 healthy subjects. Steady state was achieved rapidly, and after repeated dosing for 3 days, methylnaltrexone decreased oral‐cecal transit time from a pretreatment baseline value of 101.3 ± 29.4 min (mean ± SD) to 82.5 ± 20.7 min. Maximum observed plasma concentrations, measured 5 minutes postdose, were 538 ± 237 and 675 ± 180 ng/mL after doses 1 and 2, respectively. Based on 6‐hour sampling periods, the plasma half‐life, 2.5 ± 0.5 and 2.9 ± 0.9 hours following the 1st and 12th doses, respectively, was unchanged at steady state. There was essentially no accumulation of methylnaltrexone, based on the ratio of AUC values after doses 12 and 1. This study showed that repeated administration of intravenous methylnaltrexone is well tolerated in humans, with no significant adverse events or changes in opioid subjective ratings and no clinically noteworthy alterations in pharmacokinetics. The observation of a significant reduction in the gut transit time after repeated administration of methylnaltrexone to these opioid‐naive volunteers suggests that endogenous opioids modulate human gut motility.

Methylnaltrexone, a novel peripheral opioid receptor antagonist for the treatment of opioid side effects

Methylnaltrexone is an investigational peripheral opioid receptor antagonist, a quaternary derivative of naltrexone. Methylnaltrexone has greater polarity and lower lipid solubility, thus it does not cross the blood–brain barrier in humans. Methylnaltrexone offers the therapeutic potential to block or reverse the undesired side effects of opioids that are mediated by receptors located in the periphery (e.g., in the gastrointestinal tract), without affecting analgesia or precipitating the opioid withdrawal symptoms that are predominantly mediated by receptors in the CNS. This article reviews preclinical studies and clinical opioid bowel dysfunction trial data, and briefly discusses other potential roles of this compound in clinical practice.

A phase I dose escalation trial of vaccine replicon particles (VRP) expressing prostate-specific membrane antigen (PSMA) in subjects with prostate cancer.

PSMA-VRP is a propagation defective, viral replicon vector system encoding PSMA under phase I evaluation for patients with castration resistant metastatic prostate cancer (CRPC). The product is derived from an attenuated strain of the alphavirus, Venezuelan Equine Encephalitis (VEE) virus, and incorporates multiple redundant safety features. In this first in human trial, two cohorts of 3 patients with CRPC metastatic to bone were treated with up to five doses of either 0.9×10(7)IU or 0.36×10(8)IU of PSMA-VRP at weeks 1, 4, 7, 10 and 18, followed by an expansion cohort of 6 patients treated with 0.36×10(8)IU of PSMA-VRP at weeks 1, 4, 7, 10 and 18. No toxicities were observed. In the first dose cohort, no PSMA specific cellular immune responses were seen but weak PSMA-specific signals were observed by ELISA. The remaining 9 patients, which included the higher cohort and the extension cohort, had no PSMA specific cellular responses. PSMA-VRP was well-tolerated at both doses. While there did not appear to be clinical benefit nor robust immune signals at the two doses studied, neutralizing antibodies were produced by both cohorts suggesting that dosing was suboptimal.

Randomized, Double-Blind Trial of Oral Methylnaltrexone for the Treatment of Opioid-Induced Constipation in Patients with Chronic Noncancer Pain

Subcutaneous methylnaltrexone, a peripherally acting μ‐opioid receptor antagonist, improves opioid‐induced constipation (OIC) in patients with chronic noncancer pain. An oral methylnaltrexone formulation has been developed.

Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC): A phase I trial in metastatic castration-resistant prostate cancer (mCRPC) previously treated with a taxane.

119 Background: The abundant expression of prostate specific membrane antigen (PSMA) on prostate cancer cells provides a rationale for antibody therapy. PSMA ADC, a fully human antibody to PSMA linked to the microtubule disrupting agent monomethyl auristatin E (MMAE), binds PSMA and is internalized within the prostate cancer cell where cleavage by lysosomal enzymes release free MMAE, causing cell cycle arrest and apoptosis. We have completed a phase 1 dose escalation study of PSMA ADC in subjects with taxane-refractory mCRPC. METHODS Eligibility requirements include progressive mCRPC following taxane-containing chemotherapy and ECOG status of 0 or 1. PSMA ADC was administered by IV infusion Q3W for up to 4 cycles. Safety, pharmacokinetics (PK), PSA, circulating tumor cells (CTC), clinical disease progression and immunogenicity to PSMA ADC were assessed. Serum PSMA ADC and total antibody were measured by ELISA, and free MMAE was measured by LC/MS/MS.The dosing cohorts ranged from 0.4 mg/kg to 2.8 mg/kg. RESULTS 52 subjects with mCRPC were dosed in nine dose levels. All subjects received prior docetaxel, 5 also received cabazitaxel and 3 subjects also received paclitaxel. PSMA ADC was generally well tolerated with the most commonly seen adverse events being anorexia and fatigue. Peripheral neuropathy was reported by 7 subjects after repeated doses. Two were grade 3. Dose limiting toxicities (DLT) seen at 2.8 mg/kg were neutropenia (one death) and reversible liver function tests (LFTs) elevations. Antitumor activity was manifested as reductions either in PSA or CTCs at ≥ 1.8 mg/kg PSMA ADC in approximately 50% of patients. Exposure to PSMA ADC increased with dose and was ~1,000-fold greater than MMAE exposure and no accumulation was observed. CONCLUSIONS PSMA ADC in this study was generally well tolerated in doses up to 2.8 mg/kg every three weeks in subjects with mCRPC, previously treated with taxane. Antitumor activity was seen at higher dose levels. DLTs were neutropenia and reversible LFT abnormalities. The maximum tolerated dose of PSMA ADC was determined to be 2.5 mg/kg. A phase 2 trial in taxane refractory mCRPC has been initiated. CLINICAL TRIAL INFORMATION NCT01414283.

Methylnaltrexone reduces oral-cecal transit time in humans

using Wilcoxons Signed Rank test. Results: The baseline serum leptin levels were 2.6 +/2.4 ng/mh Three days after leptin administration the serum levels wetz 2111.4 +A 555.1 ng/ml (P<0.C~1). No sigmficant difterences in gastric emptying could be observed. At baseline T1/2 was 98.9 +l559 rain and Tlag was 51.8 +/37 rain Three days after leptin administration T1/2 was 81.0 +/34.5 min and Tlag was 29.9 +/24.5 m m Pvalues were 031 and 0.11, respectively. Conclusions: Although there was a trend towards an accelerated gastric emptying, administration of 80 nag PEG-OB does trot significantly aifect the gastric emptying rate of a solid meal. *Hukshom et al. 2000 J Clin Endocrinol Metab 85:4003-4009.

Protease inhibitor-induced nausea and vomiting is attenuated by a peripherally acting, opioid-receptor antagonist in a rat model

BackgroundProtease inhibitors such as ritonavir can cause nausea and vomiting which is the most common reason for discontinuation. Rats react to nauseous and emetic stimuli by increasing their oral intake of non-nutritive substances like kaolin, known as pica behavior. In this study, we evaluated the effects of methylnaltrexone, a peripherally acting mu-opioid receptor antagonist that does not affect analgesia, on ritonavir-induced nausea and vomiting in a rat pica model.ResultsWe observed that 24 to 48 hr after administration of oral ritonavir 20 mg/kg, kaolin consumption increased significantly in rats (P < 0.01). This increase was attenuated by pretreatment with an intraperitoneal injection of methylnaltrexone (0.3–3.0 mg/kg) in a dose dependent manner (P < 0.01) and also with naloxone (0.1–0.3 mg/kg) (P < 0.01). The areas under the curve for kaolin intake from time 0 to 120 hr were significantly reduced after administration of the opioid antagonists. Food intake was not significantly affected. Plasma naltrexone levels were measured after methylnaltrexone injection, and no detectable levels were found, indicating that methylnaltrexone was not demethylated in our experimental paradigm.ConclusionThese results suggest that methylnaltrexone may have potential clinical utility in reducing nausea and vomiting in HIV patients who take ritonavir.

Effects of Anesthetics on Cancer Recurrence

TO THE EDITOR: We read with great interest the recent article by Weckermann et al on the perioperative activation of disseminated tumor cells in bone marrow of patients with prostate cancer. The authors postulate “unknown perioperatively acting triggers that stimulate outgrowth of DTCs” (disseminated tumor cells). Recent clinical and laboratory data suggest that anesthetic technique may play a role in tumor dissemination and recurrence. This issue has been highlighted in the anesthesia literature in a recent article of the Anesthesia Patient Safety Foundation Newsletter, which reviews the clinical and laboratory data for such an effect. In a retrospective study of prostate cancer, there was a significant difference in the rate of tumor recurrence contingent on the type of anesthesia used. A small retrospective study in breast cancer had similar findings. A large, multicenter, prospective, randomized trial investigating the influence of type of anesthesia on breast cancer recurrence is currently underway. In addition to the clinical studies, there is also an evolving basic science literature suggesting that opiates affect tumor growth. Both we and Gupta et al have shown that clinically relevant concentrations of opiates can cause endothelial cell proliferation and migration in vitro. The proangiogenic effect of mu opioid agonists seems to be the result of reciprocal transactivation of the vascular endothelial growth factor receptor. We have also demonstrated that mu opioids induce a defect in barrier function, potentially allowing penetration of tumor cells. The effects of mu agonists on both angiogenesis and barrier function are reversed by tertiary opiate antagonists or by methylnaltrexone, a peripherally acting mu opioid receptor antagonist approved in the United States to treat opioid-induced constipation in patients with advanced illness receiving palliative care when response to laxatives has not been sufficient. If these laboratory studies are confirmed clinically, then the selection of anesthetic technique used during the operative procedure and the possible use of peripheral mu opioid receptor antagonists in the perioperative period may be of potential importance. It would be particularly interesting if the authors were able to review the perioperative records of their patients to see which drugs were administered and what anesthetic techniques were used. We commend the authors for their diligent work and believe that their observations deserve additional investigation.

Methylnaltrexone: A Peripherally Acting Opioid Antagonist

Opioids are widely used analgesics in patients with moderate or severe pain. Their effectiveness for pain relief is often limited, however, by the most frequently occurring side effect, opioid-induced constipation. Unlike the analgesic effects of opioids, which are centrally mediated, constipation is mediated mainly by peripheral opioid receptors in the gut. Conventional laxatives are often ineffective in treating opioid-inducded constipation. Methylnaltrexone is a novel quaternary derivative of naltrexone that does not cross the blood—brain barrier in humans and acts as a selective peripheral opioid receptor antagonist, recently approved by the FDA and other regulatory agencies for the treatment of opioid-induced constipation in patients with advanced illness receiving palliative care. This chapter reviews preclinical studies and data from trials of methylnaltrexone bowel dysfunction induced by opioids. Other potential clinical roles for methylnaltrexone are also briefly presented.

Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC): A phase I trial in men with prostate cancer previously treated with taxane.

107 Background: The abundant expression of prostate specific membrane antigen (PSMA) type II transmembrane glycoprotein on prostate cancer cells provides a rationale for antibody therapy. PSMA ADC, a fully humanized antibody to PSMA linked to the potent antitubulin agent monomethyl auristatin E (MMAE), binds PSMA and is internalized within the prostate cancer cell where cleavage and release of free MMAE occur, causing cell cycle arrest and apoptosis. We report results from an ongoing phase 1 dose escalation study of PSMA ADC in patients (pts) with taxane-refractory metastatic castration-resistant prostate cancer (metCRPC). METHODS Eligibility requirements include metCRPC after taxane-containing regimen and ECOG status of 0 or 1. PSMA ADC was administered by IV infusion Q3W for up to 4 cycles. Adverse events, PK, PSA, circulating tumor cells, clinical disease progression and immunogenic response to PSMA ADC were assessed. Serum PSMA ADC and total antibody were measured by ELISA, and free MMAE was measured by LC/MS/MS. Dosing cohorts have ranged from 0.4 mg/kg to 2.2 mg/kg. RESULTS 26 pts have enrolled in six dosing cohorts (0.4, 0.7, 1.1, 1.6, 1.8, 2.0 mg/kg). Treatment has to date been generally well tolerated with the most commonly seen adverse event being fatigue and the most common laboratory abnormalities being reversible changes in liver and hematological parameters. Antitumor activity manifested as reductions in PSA, circulating tumor cells and/or bone pain has been observed in the higher dose cohorts and appears to be dose-related. Exposure to PSMA ADC increased with dose and was ∼1,000-fold greater than MMAE exposure. Similar PK metrics were observed after the first and third doses. Dosing at the 2.2 mg/kg cohort is continuing and an MTD has not yet been reached. CONCLUSIONS In pts with metCRPC previously treated with taxane PSMA ADC has exhibited dose-related antitumor activity. The MTD has not yet been reached and enrollment is ongoing at higher dose levels.