Subcutaneous administration of biotherapeutics: current experience in animal models.

In recent years, many peptide- and protein-based biotherapeutics have been approved for subcutaneous (SC) delivery. The mechanisms and factors affecting the uptake and distribution of such large molecules following SC administration are not well understood. This review outlines the factors influencing uptake, transport, distribution and species differences following the SC administration of biotherapeutics; improved understanding of these factors will facilitate the appropriate selection of animal models and improve predictivity for the bioavailability of drugs in humans. Morphological differences between species, such as the presence or absence of the panniculus carnosus muscle, may have significant effects on SC delivery. Following SC administration, small molecules, peptides and small proteins (< or = 16 kDa) primarily diffuse through the blood vessel walls directly into capillaries, whereas large molecules are taken up into the more porous lymphatics. Critical parameters that may impact the availability in blood of compounds administered SC, other than molecular weight, include host-related factors, such as animal motility, age and gender, structural and functional characteristics of the SC interstitium and the lymphatics, and extrinsic factors, such as anesthesia, injection technique, potential precipitation or degradation at the injection site, and the use of SC delivery technology. A review of regulatory approval information for SC administered biotherapeutics is provided for comparison. Careful control of parameters during SC administration will reduce inter-individual and inter-species variability.

Barusiban, an effective long-term treatment of oxytocin-induced preterm labor in nonhuman primates.

Preterm labor (PTL) affects up to 25% of human pregnancies in developing countries, but there are few therapeutic options. Based on the key role of oxytocin (OXT) in labor and parturition, OXT antagonists are a potentially useful class of drugs for PTL. Barusiban is a new selective, potent, and long-acting OXT receptor antagonist. In this study barusiban was given by continuous i.v. infusion to monkeys during the last 3 wk of pregnancy; the monkeys were also given daily doses of OXT to induce uterine contractions and simulate PTL. Barusiban effectively suppressed OXT-induced PTL-like contractions and prevented early delivery. In contrast, fenoterol (a beta2-adrenoceptor [beta2-AR] agonist used as a comparative control) did not inhibit uterine contractions in this model. Barusiban was particularly effective in maintaining low intrauterine pressure (IUP) near the end of pregnancy, which is when IUP in both OXT controls and fenoterol-treated females increased substantially. Although barusiban delayed the onset of labor, it did not prevent normal delivery. These data demonstrate the safety and efficacy of barusiban in reducing uterine contractility in response to repeated OXT challenge, and suggest that barusiban may be therapeutically effective in long-term treatment of PTL.

Barusiban, a new highly potent and long-acting oxytocin antagonist: pharmacokinetic and pharmacodynamic comparison with atosiban in a cynomolgus monkey model of preterm labor.

Preterm labor (PTL) represents a significant unmet clinical need that affects up to 20% of all pregnancies and is a leading cause of preterm delivery and associated neonatal morbidity and mortality. Therapeutic options are limited, with existing drug therapy (tocolytics) compromised by side effects and limited efficacy. Because oxytocin (OT) is likely to be involved causally in PTL, this study compared two OT receptor antagonists, barusiban and atosiban, for their tocolytic effects. OT was given to instrumented pregnant cynomolgus monkeys to induce contractions and simulate PTL. Barusiban or atosiban was then given iv (bolus or infusion) to evaluate inhibitory effects on uterine contractions, measured by telemetric recording of intrauterine pressure. Both antagonists had high efficacy (96-98% inhibition of intrauterine pressure) and rapid onset of action (0.5-1.5 h). Barusiban was three to four times more potent than atosiban, which was attributed to its higher affinity and selectivity for the OT receptor. Barusiban also had a much longer duration of action (>13-15 h, compared with 1-3 h for atosiban). The inhibitory effects of barusiban were reversible within 1.5-2.5 h by high-dose OT infusion. Overall, barusiban's improved potency, long duration of action, and reversibility may provide an improved tocolytic for treatment of PTL.

Telemetric uterine contraction model in preterm cynomolgus monkeys.

A telemetric-based model is presented for evaluation of uterine contractions and preterm labor (PTL) in pregnant cynomolgus monkeys. The model allows continuous monitoring of electromyography (EMG) and intrauterine pressure (IUP) as indicators of uterine activity. A pressure sensor was implanted into the amnion of pregnant monkeys on gestational day (GD) 120 +/- 3 and biopotential sensors were attached to the uterus. A telemetry transmitter was placed in a subcuticular pocket located in the flank. Venous catheters were tethered to the next room for dosing and blood sampling without disturbing the conscious animals. EMG and/or IUP were monitored continuously post-operatively. IUP is a reliable parameter for monitoring intrauterine activity, as demonstrated by a close relationship between bursts of activity in the EMG and increases in IUP. Animals close to term showed a basal level of uterine activity during the daytime, with irregular contractions of <10 mmHg. In the night, spontaneous contractions (10-40 mmHg; maximum between 18:00 and 01:00 h) appeared every 3-6 min. Artificial contractions of 15-40 mmHg that mimicked preterm labor were induced at any time of the day by infusion of 5-60 mU oxytocin (OT) per kilogram per hour. These contractions showed a dose-dependent response to OT, and were stable for up to 14 h of constant infusion of OT. Following withdrawal of oxytocin, contractions returned to baseline within 1h. No desensitization of oxytocin-induced contractions was observed when oxytocin was administered daily for up to several weeks. This telemetric model characterizes uterine contractions in non-human primates and provides an excellent method to evaluate pharmacological characteristics of drug candidates intended to treat PTL.