Biofarmacevtsko in klinično vrednotenje generičnega mazila s kalcipotriolom in betametazonom : doktorska disertacija

Habjanič, Nina (avtor), Kerec Kos, Mojca (mentor), Kristan, Katja (komentor)

Doktorska disertacija zajema biofarmacevtsko in klinično vrednotenje generičnega mazila (Lek d.d.), ki vsebuje učinkovini kalcipotriol monohidrat in betametazon dipropionat in je namenjeno lokalnemu zdravljenju luskavice v plakih. Mazilo ima enako kvalitativno in kvantitativno sestavo zdravilnih učinkovin ter je v enaki farmacevtski obliki kot inovativno zdravilo Daivobet® (Leo Pharma A/S), vendar se od inovativnega mazila razlikuje v pomožnih snoveh. Biofarmacevtsko smo mazilo ovrednotili z in vitro metodami, s katerimi smo proučevali sproščanje ter permeabilnost kalcipotriola in betametazona iz mazilne podlage. Klinično (in vivo) smo ovrednotili učinkovitost in varnost generičnega mazila v klinični študiji faze III na bolnikih s kronično luskavico v plakih. Pri bolnikih z luskavico se pogosteje pojavljajo nekatere sočasne bolezni, zato smo na podlagi podatkov, pridobljenih v klinični študiji, ocenili demografske in klinične parametre, ki pri teh bolnikih značilno vplivajo na učinkovitost lokalnega zdravljenja s kalcipotriol-betametazon mazilom. Takšna analiza je po razpoložljivih podatkih dostopna le za bolnike z zmerno do hudo obliko bolezni v primeru sistemske terapije luskavice. Rezultate in vitro testov dermalne absorpcije smo primerjali z rezultati klinične učinkovitosti in varnosti z namenom oceniti občutljivost in vitro metod in njihovo in vivo napovedno vrednost, kar še ni bilo predstavljeno za mazilo, ki vsebuje kombinacijo kalcipotriola in betametazona. V okviru doktorske naloge smo pokazali, da je generično kalcipotriol-betametazon mazilo (Lek d.d.) učinkovito pri zdravljenju luskavice v plakih, kar smo ovrednotili z odstotno spremembo modificiranega indeksa izraženosti luskavice in velikosti prizadete površine kože (mPASI). Po 4-tedenskem zdravljenju je mazilo znižalo povprečne vrednosti mPASI za 80,7 %. Učinkovitost generičnega mazila so potrdili tudi rezultati sekundarnih spremenljivk. Izvedena klinična študija faze III na bolnikih s kronično luskavico v plakih je dovolj občutljiva, da je pri zdravljenju luskavice zanesljivo zaznala razlike v učinkovitosti med vehiklom in kalcipotriol-betametazon mazilom. Razlika v povprečnem zmanjšanju mPASI med testnim mazilom in vehiklom je znašala 31,5 odstotnih točk, prav tako pa je bilo testno mazilo značilno bolj učinkovito kot vehikel po 4 tednih zdravljenja v vseh sekundarnih spremenljivkah učinkovitosti. S tem smo pokazali, da sta načrt klinične študije terapevtske ekvivalence ter izbrana populacija ustrezna glede na namen študije. Analiza neželenih učinkov je pokazala, da so bolniki zdravljenje z generičnim mazilom dobro prenašali. Prav tako nismo zaznali tveganja za sistemsko varnost, povezanega z morebitno sistemsko absorpcijo kalcipotriola ali betametazona, ki bi se odražala v klinično pomembni spremembi za albumin korigiranega serumskega kalcija ali 24-urnega kortizola v urinu. Dokazali smo, da indeks telesne mase pomembno vpliva na odstotek znižanja mPASI ter PASI75 (vsaj 75 % zmanjšanje mPASI) po 4-tedenskem zdravljenju, pri čemer se uspešnost zdravljenja znižuje z naraščanjem le-tega. Značilnosti luskavice niso vplivale na uspešnost zdravljenja, smo pa zaznali pomemben vpliv debelosti in ostalih srčno-žilnih bolezni (aritmija, srčna kap/ishemija, angina, atrijska fibrilacija in koronarna arterijska bolezen), ki občutno zmanjšujejo odstotno spremembo mPASI po 4-tedenskem zdravljenju. Pokazalo se je tudi, da je pri bolnikih z debelostjo kar 2-krat manjša verjetnost za dosego PASI75. Obstaja korelacija med starostjo ob izbruhu bolezni in telesno težo, kar nakazuje na to, da je povečana telesna teža dejavnik tveganja za pojav luskavice. V zadnjem delu naloge smo pokazali, da pri kalcipotriol-betametazon mazilu obstaja povezava med in vitro parametri sproščanja ter permeabilnosti zdravilnih učinkovin iz mazilne podlage ter in vivo parametri klinične učinkovitosti in varnosti. Izvedeni testi sproščanja in permeabilnosti konsistentno kažejo višji tok kalcipotriola in betametazona ter večjo permeabilnost učinkovin iz testnega mazila v primerjavi z referenčnim. Pokazali smo, da za lipofilne učinkovine rožena plast kože ne predstavlja glavne bariere pri absorpciji, pač pa je omejujoč dejavnik porazdeljevanje zdravilne učinkovine iz mazila. Večja hitrost dermalne absorpcije in vitro iz testnega mazila se je odražala na rezultatih klinične učinkovitosti, čeprav je bila razlika in vivo manj izražena in ni bila klinično pomembna. V skladu z in vitro rezultati sproščanja betametazona se je nivo 24-urnega kortizola v urinu v povprečju bolj znižal pri testnem mazilu, čeprav razlika ni značilna. Pri kalcipotriolu se opažena razlika v toku učinkovin in vitro ni odražala v spremembi vrednosti serumskega kalcija. Zaključimo lahko, da in vitro testi dermalne absorpcije rangirajo testno in referenčno mazilo v skladu z rezultati klinične študije, vendar pa zaradi njihove visoke občutljivosti zaznajo tudi razlike, ki klinično niso pomembne. Izvedena klinična študija predstavlja model za dokazovanje terapevtske ekvivalence za lokalno delujoča zdravila za luskavico v plakih, ki se lahko z ustreznimi modifikacijami uporabi tudi za dokazovanje ekvivalence drugih zdravilnih učinkovin ali farmacevtskih oblik za lokalno zdravljenje luskavice. Kot prvi smo na populaciji bolnikov z blago do zmerno luskavico preverjali vpliv bolnikovih demografskih ter kliničnih značilnosti na uspešnost zdravljenja s kalcipotriol-betametazon mazilom. Glede na dejstvo, da ima kar 80 % odstotkov bolnikov z luskavico blago do zmerno obliko bolezni, kjer je lokalno zdravljenje s kalcipotriol-betametazon mazilom terapija prvega izbora, predstavlja novo znanje o dejavnikih vpliva pomemben doprinos k zdravljenju luskavice na tej populaciji. Naloga pomembno prispeva k znanju o in vitro - in vivo korelaciji za farmacevtske oblike za dermalno uporabo, ki je pomembno za optimizacijo smernic za dokazovanje bioekvivalence za lokalno delujoča zdravila. In vitro testi sproščanja in permeabilnosti še niso rutinsko sprejeti kot metode za dokazovanje bioekvivalence, vendar pridobivajo na pomembnosti zaradi številnih dokazov o njihovi sposobnosti, da odražajo absorpcijo in vivo ter korelirajo s parametri klinične učinkovitosti. Pokazali smo, da in vitro testi dermalne absorpcije razvrstijo testno in referenčno mazilo v skladu z rezultati klinične študije, vendar pa zaradi njihove visoke občutljivosti zaznajo tudi razlike, ki klinično niso pomembne. Na podlagi tega zaključujemo, da so in vitro metode dermalne absorpcije v nekaterih primerih ustrezne za dokazovanje bioekvivalence tudi za generična zdravila, ki se od referenčnih razlikujejo v kvalitativni in kvantitativni sestavi, saj bodo zaradi visoke občutljivosti zaznale morebiten vpliv spremenjene sestave zdravila na sproščanje učinkovine iz podlage ali njeno difuzijo skozi kožo.

• Jezik: Slovenski jezik
• Ključne besede: luskavica, lokalno zdravljenje, generična mazila, kalcipotriol-betametazon mazilo, zdravilne učinkovine, sproščanje, permeabilnost, varnost, pomožne snovi, daivobet (zdravilo)
• Vrsta gradiva: Doktorska disertacija
• Tipologija: 2.08 - Doktorska disertacija
• Organizacija: FFA - Fakulteta za farmacijo
• Kraj izida: Ljubljana
• Založnik: [N. Habjanič]
• Leto izida: 2019
• Št. strani: 142 str.
• PID: 20.500.12556/RUL-137099
• UDK: 616.517-085(043.3)
• COBISS.SI-ID: 303596544
• Datum objave v RUL: 01.06.2022

Sekundarni jezik

• Jezik: Angleški jezik
• Naslov: Biopharmaceutical and clinical evaluation of generic ointment containing calcipotriol and betamethasone

Izvleček

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.