Comparative pharmacokinetics and pharmacodynamics of a PEGylated recombinant human growth hormone and daily recombinant human growth hormone in growth hormone-deficient children.

OBJECTIVE: Recombinant human growth hormone (rhGH) replacement therapy in children generally requires daily subcutaneous (sc) injections, which may be inconvenient for patients. Jintrolong® is a PEGylated rhGH with the purpose of weekly sc injections. The aim of the current study was to examine the pharmacokinetics, pharmacodynamics, safety, and tolerability of multiple sc doses of Jintrolong® vs daily doses of rhGH. DESIGN AND METHODS: Twelve children with growth hormone deficiency participated in this single-center, open-label, crossover Phase I trial. All subjects received daily sc injections of rhGH at 0.0286 mg/kg/d for 7 days, followed by a 4-week washout period and six weekly doses of Jintrolong® at 0.2 mg/kg/w. RESULTS: In comparison with rhGH, sc injection of Jintrolong® produced a noticeably higher C max, significantly longer half-life (t 1/2), and slower plasma clearance, signifying a profile suitable for long-term treatment. The ratio of the area under the concentration vs time curve (AUC) after the seventh and first injections (AUC(0-∞)7th/AUC(0-∞)1st) of rhGH was 1.02, while the AUC(0-∞)6th/AUC(0-∞)1st of Jintrolong ® was 1.03, indicating no accumulation of circulating growth hormone. There was no significant difference in the change in insulin-like growth factor-1 expression produced by 7 days of sc rhGH and weekly Jintrolong® injections. There were no severe adverse events during the trial. CONCLUSION: The elimination rate of Jintrolong® was slower than that of sc rhGH. No progressive serum accumulation of Jintrolong® was found. The changes in insulin-like growth factor-1 expression produced by rhGH and Jintrolong® were comparable, indicating similar pharmacodynamics. Our results demonstrate that Jintrolong® is suitable for long-term growth hormone treatment in children with growth hormone deficiency.

Sustained and cancer cell targeted cytosolic delivery of Onconase results in potent antitumor effects.

The unfavorable pharmacokinetics and low tumor specificity hampered the potential clinical utility of Onconase, a promising modality in anticancer treatment with unique targets and novel mechanism of action. In this study, a modular and multi-stage drug delivery system (DDS) that can break down organ (renal accumulation), cellular (cancer cell specific uptake) and sub-cellular (endosomal escape) level barriers encountered by Onconase during its long journey from injection site to the cytoplasm of cancer cell was designed. Human serum albumin fusion extended the half-life of Onconase and significantly decreased its kidney accumulation. Epithelial cell adhesion molecular (EpCAM) specific antibody fragment appending enhanced binding and internalization of Onconase toward EpCAM positive cancer cell and increased its tumor accumulation and retention. Tethering Onconase to its carrier by cleavable disulfide linker prompted endosomal escape and restored its cytotoxicity. In vivo antitumor efficacy assay in human tumor xenograft model revealed that only when the entire organ, cellular and sub-cellular level barriers had been broken down, will Onconase turn into a potent antitumor agent.

Shiga toxin type 2 (Stx2), a potential agent of bioterrorism, has a short distribution and a long elimination half-life, and induces kidney and thymus lesions in rats.

Shiga toxin type 2, a major virulence factor produced by the Shiga toxin-producing Escherichia coli, is a potential toxin agent of bioterrorism. In this study, iodine-125 (125I) was used as an indicator to describe the in vivo Stx2 biodistribution profile. The rats were injected intravenously (i.v.) with 125I-Stx2 at three doses of 5.1-127.5 µg/kg body weight. Stx2 had a short distribution half-life (t (1/2)α, less than 6 min) and a long elimination half-life in rat. The toxicokinetics of Stx2 in rats was dose dependent and nonlinear. Stx2 concentrations in various tissues were detected at 5-min, 0.5-h, and 72-h postinjection. High radioactivity was found in the lungs, kidneys, nasal turbinates, and sometimes in the eyes, which has never been reported in previous studies. In a preliminary assessment, lesions were found in the kidney and thymus.

Development and application of a real-time PCR method for pharmacokinetic and biodistribution studies of recombinant adenovirus.

A replication-deficient recombinant adenovirus (Ad5-LFA-3/IgG(1)) that encodes secreted LFA-3/IgG(1) was constructed for gene therapy treatment of psoriasis. The purpose of this study was to develop a real-time PCR method for pharmacokinetic and biodistribution studies of Ad5-LFA-3/IgG(1) within the circulation and organs. This method showed good specificity, sensitivity and reproducibility over a wide dynamic range of concentrations. Quantitative measurement of recombinant adenoviral DNA suggested that the level of Ad5-LFA-3/IgG(1) DNA in circulating blood peaked within 10 min following intravenous injection in rhesus macaques. Following this peak, the adenoviral DNA level dropped significantly to a very low level. Real-time PCR revealed that Ad5-LFA-3/IgG(1) DNA was enriched in the spleen, lung and liver after injection of the adenovirus into rats through the tail vein. The adenoviral DNA was barely detected in other tissues. These data provide important information for clinical trials of Ad5-LFA-3/IgG(1) and confirm the utility of the real-time PCR assay for monitoring gene therapy trials.