Brian M. Sadler

Biased agonism of the μ-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: A randomized, double-blind, placebo-controlled, crossover study in healthy volunteers

Summary An experimental medicine comparison of the novel biased ligand TRV130 to morphine reveals that selective signaling at the mu opioid receptor may improve opioid therapeutic index. ABSTRACT Opioids provide powerful analgesia but also efficacy‐limiting adverse effects, including severe nausea, vomiting, and respiratory depression, by activating &mgr;‐opioid receptors. Preclinical models suggest that differential activation of signaling pathways downstream of these receptors dissociates analgesia from adverse effects; however, this has not yet translated to a treatment with an improved therapeutic index. Thirty healthy men received single intravenous injections of the biased ligand TRV130 (1.5, 3, or 4.5 mg), placebo, or morphine (10 mg) in a randomized, double‐blind, crossover study. Primary objectives were to measure safety and tolerability (adverse events, vital signs, electrocardiography, clinical laboratory values), and analgesia (cold pain test) versus placebo. Other measures included respiratory drive (minute volume after induced hypercapnia), subjective drug effects, and pharmacokinetics. Compared to morphine, TRV130 (3, 4.5 mg) elicited higher peak analgesia (105, 116 seconds latency vs 75 seconds for morphine, P < .02), with faster onset and similar duration of action. More subjects doubled latency or achieved maximum latency (180 seconds) with TRV130 (3, 4.5 mg). Respiratory drive reduction was greater after morphine than any TRV130 dose (−15.9 for morphine versus −7.3, −7.6, and −9.4 h * L/min, P < .05). More subjects experienced severe nausea after morphine (n = 7) than TRV130 1.5 or 3 mg (n = 0, 1), but not 4.5 mg (n = 9). TRV130 was generally well tolerated, and exposure was dose proportional. Thus, in this study, TRV130 produced greater analgesia than morphine at doses with less reduction in respiratory drive and less severe nausea. This demonstrates early clinical translation of ligand bias as an important new concept in receptor‐targeted pharmacotherapy.

First Clinical Experience With TRV130: Pharmacokinetics and Pharmacodynamics in Healthy Volunteers

TRV130 is a G protein‐biased ligand at the µ‐opioid receptor. In preclinical studies it was potently analgesic while causing less respiratory depression and gastrointestinal dysfunction than morphine, suggesting unique benefits in acute pain management. A first‐in‐human study was conducted with ascending doses of TRV130 to explore its tolerability, pharmacokinetics, and pharmacodynamics in healthy volunteers. TRV130 was well‐tolerated over the dose range 0.15 to 7 mg administered intravenously over 1 hour. TRV130 geometric mean exposure and Cmax were dose‐linear, with AUC0–inf of 2.52 to 205.97 ng h/mL and Cmax of 1.04 to 102.36 ng/mL across the dose range tested, with half‐life of 1.6–2.7 hours. A 1.5 mg dose of TRV130 was also well‐tolerated when administered as 30, 15, 5, and 1 minute infusions. TRV130 pharmacokinetics were modestly affected by CYP2D6 phenotype: clearance was reduced by 53% in CYP2D6 poor metabolizers.TRV130 caused dose‐ and exposure‐related pupil constriction, confirming central compartment µ‐opioid receptor engagement. Marked pupil constriction was noted at 2.2, 4, and 7 mg doses. Nausea and vomiting observed at the 7 mg dose limited further dose escalation. These findings suggest that TRV130 may have a broad margin between doses causing µ‐opioid receptor‐mediated pharmacology and doses causing µ‐opioid receptor‐mediated intolerance.

Atovaquone inhibits the glucuronidation and increases the plasma concentrations of zidovudine.

The pharmacokinetic interaction between atovaquone, a 1,4‐hydroxynaphthoquinone, and zidovudine was examined in an open, randomized, three‐phase crossover study in 14 patients infected with human immunodeficiency virus. Atovaquone (750 mg every 12 hours) and zidovudine (200 mg every 8 hours) were given orally alone and in combination. Atovaquone significantly increased the area under the zidovudine concentration‐time curve (AUC) (1.82 ± 0.62 μg · hr/ml versus 2.39 ± 0.68 μg · hr/ml; p < 0.05) and decreased the oral clearance of zidovudine (2029 ± 666 ml/min versus 1512 ± 464 ml/min; p < 0.05). In contrast, atovaquone tended to decrease the AUC of zidovudine‐glucuronide (7.31 ± 1.51 μg · hr/ml versus 6.89 ± 1.42 μg · hr/ml; p < 0.1) and significantly decreased the ratio of AUC zidovudine‐glucuronide/AUC zidovudine (4.48 ± 1.94 versus 3.12 ± 1.1; p < 0.05). The maximum concentration of zidovudine‐glucuronide was significantly lowered by atovaquone (5.7 ± 1.5 versus 4.57 ± 0.97 μg/ml; p < 0.05). Zidovudine had no effect on the pharmacokinetic disposition of atovaquone. Atovaquone appears to increase the AUC of zidovudine by inhibiting the glucuronidation of zidovudine.

Pharmacokinetic Interaction between Ketoconazole and Amprenavir after Single Doses in Healthy Men

Study Objective. To determine the effects of coadministration of amprenavir and ketoconazole on the pharmacokinetics of both drugs, and to assess the utility of the erythromycin breath test (ERMBT) to predict and explain these effects.

Atovaquone suspension in HIV-infected volunteers : Pharmacokinetics, pharmacodynamics, and TMP-SMX interaction study

Study Objective. To evaluate the pharmacokinetics and safety of atovaquone suspension in volunteers infected with the human immunodeficiency virus ((HIV).

ENU mutagenesis in the mouse electrophoretic specific-locus test, 1. Dose-response relationship of electrophoretically-detected mutations arising from mouse spermatogonia treated with ethylnitrosourea

The mouse electrophoretic specific-locus test for induced germ-cell mutations, was used to determine the response of spermatogonial stem cells to a series of doses of the germ cell mutagen N-ethyl-N-nitrosourea (ENU). Male DBA/2J and C57B1/6J mice were treated with doses of 50, 100, 200 or 250 mg/kg ENU and their progeny screened for electrophoretically-detectable mutations at 32 separate loci. As expected, increasing doses of ENU led to increasing mutant frequencies. The differences in mutant frequencies between treated DBA/2J and C57B1/6J males were not statistically significant.

Clinical Pharmacology and Pharmacokinetics of Amprenavir

OBJECTIVE: To review the pharmacokinetics, pharmacodynamics, drug interactions, and dosage and administration information of amprenavir. DATA SOURCE: An extensive review of the literature (MEDLINE search from 1994 to April 2001) relating to the clinical pharmacology of the HIV protease inhibitors was conducted. Meeting abstracts or full presentations and data submitted to the Food and Drug Administration were also reviewed. STUDY SELECTION AND DATA EXTRACTION: The data on pharmacokinetics, pharmacodynamics, drug interactions, and drug resistance were obtained from in vitro studies and open-label and controlled clinical trials. DATA SYNTHESIS: Like all HIV protease inhibitors, amprenavir interrupts the maturation phase of the HIV replicative cycle by forming an inhibitor-enzyme complex, which prevents HIV protease from binding with its normal substrates (biologically inactive viral polyproteins). Amprenavir has an enzyme inhibition constant (Ki = 0.6 nM) that falls within the Ki range of the other protease inhibitors. Amprenavirs in vitro 50% inhibitory concentration (IC50) against wild-type clinical HIV isolates is 14.6 ± 12.5 ng/mL (mean ± SD). Pharmacodynamic modeling indicates that, as is the case with other protease inhibitors, the concentration—response curve for amprenavir plateaus at amprenavir trough values above the IC50 for these isolates. This exposure—activity relationship, plus such favorable pharmacokinetic parameters as a long terminal elimination half-life (7–10 h), makes amprenavir an attractive drug of choice when considering potent antiretrovirals. The higher trough exposure obtained with amprenavir coadministered with ritonavir may allow effective treatment of patients with decreased susceptibility viral isolates and once-daily dosing. Amprenavir has been approved for adults and children; the recommended capsule doses are 1200 mg twice daily for adults and 20 mg/kg twice daily or 15 mg/kg 3 × daily for children <13 years of age or adolescents <50 kg. The recommended dose for amprenavir oral solution is 1.5 mL/kg twice daily or 1.1 mL/kg 3 × daily. CONCLUSIONS: The clinical pharmacology, exposure—activity relationship, and drug resistance profile of amprenavir support the use of this potent HIV protease inhibitor in combination antiretroviral regimens, especially for persons who have experienced virologic failure while on protease inhibitor—containing regimens.

Prolonged, But Not Diminished, Zidovudine Absorption Induced by a High‐Fat Breakfast

Study Objective. To determine the effect of a high‐fat breakfast on single‐dose, zidovudine (ZDV) pharmacokinetics.

Developmental toxicity of 1,1,1-trichloroethane in CD rats

1,1,1-Trichloroethane (TCEN), a major industrial and household solvent, was evaluated for pre- and postnatal developmental effects in Sprague-Dawley rats. This study was designed to assess the repeatability of a report (S.C. Dapson, D.E. Hutcheon, and D. Lehr, Teratology 29, 25A, 1984) that indicated that 10 ppm TCEN in drinking water caused cardiac malformations in developing rats. In the present study, TCEN (97% pure) was administered in the drinking water at target concentrations of 3, 10, and 30 ppm, using 0.05% Tween 80 as an emulsifying agent. Two control groups, one receiving deionized/filtered water and the other receiving a vehicle control solution containing 0.05% Tween 80 and 0.9 ppm 1,4-dioxane, a stabilizing agent found in the bulk chemical, were also included. Male and female breeders (more than 30 per group) were exposed to the control solutions or test compound for 14 consecutive days prior to cohabitation and for up to 13 days during the cohabitation phase. Sperm-positive females (24-29 per group) continued to be exposed to these formulations during pregnancy and lactation to Postnatal Day (PND) 21. Parental animals exhibited a slight aversion to the 30-ppm drinking water during the premating exposure. No significant effect on reproductive competence of the parental animals or postnatal growth and development of the offspring to PND 21 was noted. A slight increase in mortality from implantation to PND 1, possibly due to high mortality in one litter, was observed in the 30-ppm dose group. There was no indication of an increase in the incidence of cardiac or other malformations in PND 21 pups. In summary, TCEN administered at 3, 10, and 30 ppm in the drinking water had no significant effect on the morphological development of CD rats.

Effect of model trauma on the turnover of protein and hemoprotein components of hepatic microsomal membrane in immature rats.

Administration of 14C-leucine and delta-[3,5-3H]-aminolevulinic acid to immature male rats leads to the incorporation of radioactivity into microsomal protein, including the hemoprotein cytochrome P-450. Non-hepatic regional ischemic trauma results in an increase in the half-life of total microsomal protein, but does not exert the same effect on microsomal heme-associated protein. Loss of radioactivity from microsomal hemoprotein, primarily cytochrome P-450, from traumatized animals exhibits a biphasic pattern similar to that in control animals. The half-life of both the fast-phase component and the slow-phase component is unchanged by trauma. Trauma does, however, increase the ratio of the fast- to slow-phase components of microsomal heme. A significant increase in heme oxygenase activity after trauma suggests that the fast-phase component of hepatic microsomal cytochrome P-450 is more extensively degraded.