In doctoral thesis we biopharmaceutically and clinically evaluated the generic ointment (Lek d.d.), containing calcipotriol monohydrate and betamethason dipropionate and is indicated for topical treatment of plaque psoriasis. The generic ointment has qualitatively and quantitatively equivalent composition of active ingredients and the same dosage form as the innovator Daivobet® (Leo Pharma A/S), but it differs from the inovator in excipients. The ointment was biopharmaceutically evaluated using in vitro methods, to determine the release of calcipotriol and betamethasone from the vehicle and their skin permeation. Clinical (in vivo) assessment of efficacy and safety of generic ointment was performed in the phase III clinical study on patients with chronic plaque psoriasis. Patients with psoriasis show a distinct pattern of associated diseases, so based on the results obtained in clinical study, we evaluated demographic and clinical parameters that significantly affect the efficacy of topical treatment with calcipotriol-betamethasone ointment. Based on the available data, such analyses have only been performed for systemic treatment of patients with moderate to severe psoriasis. We compared the results of in vitro dermal absorption with the results of clinical efficacy and safety with the aim to evaluate the sensitivity of in vitro methods and their in vivo relevance, which has not been published for the ointment containing a combination of calcipotriol and betamethasone yet. We proved that generic calcipotriol-betamethasone ointment (Lek d.d.) is effective in the treatment of plaque psoriasis, as determined by the percentage reduction in modified Psoriasis Area and Severity Index (mPASI) after 4 weeks of treatment. Mean mPASI reduction after 4-week treatment was 80.7 %. The efficacy of generic ointment was also confirmed by the secondary endpoints. Perfomed phase III clinical study had sufficient sensitivity for a reliable detection of differences in the efficacy between the vehicle and calcipotriol-betamethasone ointment. The mean response difference between the test and vehicle was 31.5 percentage points, and the test product was superior to vehicle in all secondary endpoints after 4 weeks of treatment. With this we have proven that selected design of therapeutic equivalence study and study population are appropriate for the purpose of the study. The safety assessment has shown that treatment with generic ointment was well tolerated. Moreover, the results provided no concern for systemic safety caused by potential systemic absorption of calcipotriol or betamethasone, established by clinically insignificant change in albumin-corrected serum calcium levels and in total amount of cortisol excreted in 24-hour urine. We have shown that body mass index significantly affects percentage mPASI reduction and PASI75 (at least 75 % reduction in mPASI) after 4 weeks of treatment, with a trend for lower response rates with increasing body mass index. Characteristics of psoriasis did not have an impact on treatment response. However, presence of other cardiovascular diseases (rrhythmia, myocardial infarction/ischaemia, angina, atrial fibrillation and coronary artery disease) significantly reduced the mean percentage change in mPASI after 4 weeks of treatment in affected patients. Odds of achieving PASI75 is 2-times lower in obese patients. There is a correlation between age at disease onset and body weight, suggesting that increased body weight is a contributing factor to disease onset.
In the last chapter of the thesis, we have established a relationship between in vitro parameters of drug release and permeation and in vivo parameters of clinical efficacy and safety. The release and permeation tests consistently show a significantly higher release and permeation of calcipotriol and betamethasone from the test ointment compared to the reference product. Higher in vitro release and permeation rates from the test formulation were reflected in the efficacy results from the therapeutic equivalence study. However, these differences were less pronounced in vivo and were shown not to be clinically relevant. In line with the results of in vitro release for betamethasone, a decrease in 24-hour urinary cortisol was greater although not statistically significant with the test product. A change in the flux of calcipotriol in vitro was not reflected in the change of serum calcium level. Importantly, the results of in vitro release and permeation experiments rank orderly correlated with the results of clinical endpoint study, however, due to their high sensitivity, detected differences were not clinically significant. Presented clinical study is a model therapeutic equivalence study for locally acting products for the treatment of plaque psoriasis that can, with certain modifications, be used for a bioequivalence testing of other active ingredients or dosage forms for topical treatment of psoriasis. We were the first to evaluate the impact of patient’s demographic and clinical characteristics in patients with mild to moderate psoriasis on the treatment response to calcipotriol-betamethasone ointment. Considering a fact that 80 % of psoriasis patients have a mild to moderate form of disease for which topical treatment with calcipotriol-betamethasne ointment is a treatment of choice, this knowledge on risk factors presents an important contribution to psoriasis treatment in this population. Our work importantly contributes to the knowledge on the in vitro - in vivo correlation for topical drug products, which is relevant for the optimisation of bioequivalnce quidelines for locally acting products. In vitro release and permeation tests are not routinelly accepted as methods for the determination of bioequivalence, however increasing evidence is available on their capability to predict in vivo absorption and to correlate with efficacy parameters. We have shown that in vitro dermal absorption tests rank orderly correlated with the results of clinical study, however due to their high sensitivity they detect also differences that are clinically not relevant. Based on this, we conclude that in certain circumstances, in vitro dermal absorption tests can be used for bioequivalence testing also for generic products that differ from the reference product in their qualitative and quantitative composition, as due to high sensitivity, they are capable to detect potential impact of composition changes on the drug release and skin permeation.
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