No abstract

Studies were conducted to examine the absorption and disposition kinetics of insulin in dogs following intravenous (IV) and subcutaneous (SC) administration of commercial preparations. After IV and SC dosing, the plasma levels were described by models which considered basal insulin level contributions. Intersubject variation in the disposition kinetics was small with half-lives of 0.52 +/- 0.05 h and total body clearances of 16.21 +/- 2.08 ml min-1 kg-1. Calculated insulin plasma secretion rates in the canines were 14.4 +/- 3.3 mUh-1 kg-1. Following SC injection of regular insulin, the rate and extent of absorption were noted to be quite variable. The absorption process appeared first-order with half-life values of 2.3 +/- 1.3 h and extents of absorption of 78 +/- 15 per cent with a range of 55-101 per cent. Insulin absorption from SC NPH preparations was evaluated as being composed of two zero-order release phases, a rapid and a slow release phase. With a dose of 1.65 U kg-1, the rapid release phase had an average duration of 1.5 h and a rate of 580 +/- 269 mUh-1 (4.2 per cent of dose) while the slow phase had a zero-order rate of 237 +/- 92 mU h-1 which continued beyond 12 h. The extent of absorption from the NPH preparation was 23.6 +/- 5.1 per cent and was significantly lower than that for the regular injection.

CPG 7909 belongs to a new class of chemically defined CpG immunomodulators that target dendritic cell TLR9 receptors inducing IL-12, IFN-gamma, and NK cell function. The rate and durability of response to CPG 7909 was investigated in refractory patients with recurrent or advanced CTCL, who had failed one or more systemic therapies. Dose escalation with weekly sc dosing of patients at 0.08, 0.16, 0.24, or 0.28 mg/kg (3 patients/cohort) for 24 weeks is nearing completion. Additional patients continue to receive treatment at 0.32 (4 patients) or 0.36 mg/kg (12 patients). Clinical response, monitored by Composite Assessment of Index Lesion Disease Severity (CA) and Physician’s Global Assessment of Clinical Condition, has been documented. Of 28 patients enrolled, 7 (25%) have achieved objective clinical response, 5 with partial response (PR) and 2 with complete response (CR). Eleven patients have maintained stable disease (SD), while 10 have had progressive disease (PD). Eight patients have completed 24 weeks of treatment (5 SD, 2 PR, 1 CR) with 12–16 weeks of response while on study. Six patients (3 SD, 2 PR,1 CR) are currently ongoing in the study. Three patients (2 PR, 1 SD) continue to receive long term CPG 7909 at 0.12 mg/kg (58 total doses), 0.28 mg/kg (34 total doses) or 0.32 mg/kg (29 total doses) in a follow on protocol. Responses have been maintained up to 46 weeks. Weekly doses up to 0.36 mg/kg have been well tolerated. Most reported adverse events have been of CTC grade 1 or 2. The most common are dose-related local injection site reactions (erythema, induration, edema, inflammation and pain) and mild or moderate flu-like symptoms (fatigue, rigors, fever, arthralgia). Four patients had CTC grade 3 drug related AEs: one decreased lymphocyte count (0.08 mg/kg), one increased gamma glutamyl transferase (0.16 mg/kg), one decreased absolute polys (0.36 mg/kg) and one fatigue (0.36 mg/kg). Enrollment in the phase II portion of the study is ongoing and compares results of patients randomized to receive either 10 mg or 25 mg sc weekly for 24 weeks (equating to effective doses seen in dose escalation). Clinical Response with CPG 7909 - 16 M, 12 F Dose N Disease Stage CR PR SD PD 0.36 mg/kg 12 IB (7), IIB, III (3), IVA 0 2 6 4 0.32 mg/kg 4 IIA, IIB, IVA (2) 1 0 1 2 0.28 mg/kg 3 IB (2), III 0 1 2 0 0.24 mg/kg 3 IB, IIB (2) 0 1 1 1 0.16 mg/kg 3 IB (2), IIA 1 1 1 0 0.08 mg/kg 3 IB (2), IVA 0 0 0 3 28 7% 18% 39% 36%