Pharmacokinetics of recombinant human growth hormone administered by cool.click 2, a new needle-free device, compared with subcutaneous administration using a conventional syringe and needle.

BACKGROUND: Growth hormone (GH) is used to treat growth hormone deficiency (GHD, adult and paediatric), short bowel syndrome in patients on a specialized diet, HIV-associated wasting and, in children, growth failure due to a number of disorders including Turner's syndrome and chronic renal failure, and in children born small for gestational age. Different brands and generic forms of recombinant human growth hormone (r-hGH) are approved for varying indications in different countries. New ways of administering GH are required because the use of a needle and syringe or a device where a patient still has to insert the needle manually into the skin on a daily basis can lead to low adherence and sub-optimal treatment outcomes. The objective of this study was to assess the relative bioavailability of r-hGH (Saizen, Merck Serono) administered by a new needle-free device, cool.click 2, and a standard needle and syringe. METHODS: The study was performed with 38 healthy volunteers who underwent pituitary somatotrope cell down-regulation using somatostatin, according to a randomized, two-period, two-sequence crossover design. Following subcutaneous administration of r-hGH using cool.click 2 or needle and syringe, pharmacokinetic parameters were analysed by non-compartmental methods. Bioequivalence was assessed based on log-transformed AUC and C(max) values. RESULTS: The 90% confidence intervals for test/reference mean ratio of the plasma pharmacokinetic variables Cmax and AUC(0-inf) were 103.7-118.3 and 97.1-110.0, respectively, which is within the accepted bioequivalence range of 80-125%. r-hGH administered by cool.click 2 is, therefore, bioequivalent to administration by needle and syringe with respect to the rate and extent of GH exposure. Treatment using cool.click 2 was found to be well tolerated. With cool.click 2 the tmax was less (3.0 hours) than for needle and syringe delivery (4.5 hours), p = 0.002 (Friedman test), although this is unlikely to have any clinical implications. CONCLUSION: These results demonstrate that cool.click 2 delivers subcutaneous r-hGH exposure that is bioequivalent to the conventional mode of injection. The new device has the additional advantage of being needle-free, and should help to increase patient adherence and achieve good therapeutic outcomes from r-hGH treatment.

A pharmacokinetic/pharmacodynamic model for a platelet activating factor antagonist based on data arising from Phase I studies.

A nonlinear mixed-effects modelling approach was used to analyse pharmacokinetic and pharmacodynamic data from two Phase I studies of a platelet activating factor (PAF) antagonist under development for the treatment of seasonal allergic rhinitis. Data for single-dose (8 subjects) and multiple-dose (9 subjects) administration were available for analysis with a program based on an EM algorithm. Pharmacokinetic analyses of plasma drug concentrations were performed using a biexponential model with first-order absorption. PAF response data were modelled with a hyperbolic Emax model. The drug showed nonlinear pharmacokinetics, with the clearance decreasing from 46.0 to 27.1 L h(-1) over a dose range of 160-480 mg. There was an apparent dose dependency within the C50 (concentration producing 50% of the maximum effect) but at higher doses most of the data was above the estimated C50 and when the data was analysed simultaneously a value of 17.57 ng mL(-1) was obtained for C50, with considerable intersubject variability (103%). Consistent results were obtained from the two studies and the population and individual pharmacodynamic parameter estimates from the analyses provided predicted responses that were in good agreement with the observed data. The results were used to simulate a 320-mg twice-daily dosing regimen.