Effects of salt forms on the oral absorption of highly permeable weak base doxazosin

doctoral thesis

• Title (croatian): Utjecaj različitih soli visoko permeabilne slabe baze doksazosina na oralnu apsorpciju
• Author: Marijana Erceg
• Mentor: Biserka Cetina Čižmek (mentor)
• Mentor: Christos Reppas (komentor); strani drzavljanin: XXXXXXXXX
• Committee member: Branka Zorc (predsjednik povjerenstva)
• Committee member: Biserka Cetina Čižmek (član povjerenstva)
• Committee member: Franjo Plavšić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; Zagreb
• Defense date and country: 2011-12-08, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy
• Universal decimal classification (UDC): 615 - Pharmacology. Therapeutics. Toxicology

Abstract

In this study, the usefulness of biorelevant in vitro data and of canine data in forecasting early exposure after the
administration of two phases of a BCS Class II compound, i.e., doxazosin base (DB) and its mesylate salt (DM)
was evaluated. DB, DM, and doxazosin hydrochloride (DH) were prepared and extensively characterized.
The solubility of prepared substances was tested in vitro in various media, including human aspirates, using the
shake flask method. Dissolution experiments were performed in simple buffer media and biorelevant media
simulating gastric and intestinal fluids in the fasted and fed state. Pharmacokinetic (PK) studies were performed
in dogs with DB and DM tablets in the fasting and fed state, while the results form human PK study on DM
tablets in the fasted state were available from previous Pliva´s study. Analytical method for determination of
doxazosin in canine plasma was developed and validated using canine samples collected in the fed state in order
to assure the suitability of the method for measurement of low concentrations of doxazosin in plasma and high
specificity of the method despite the number of interfering compounds in the fed state plasma samples.
Solubilities of DB and DM in human gastric fluid were forecasted by data in fasted state simulating gastric fluid
containing physiological components (FaSSGF-V2) but not by data in HClpH 1.8. Unlike data in FaSSGF-V2,
dissolution of DB and DM tablets in HClpH 1.6 is rapid. Dissolution of DB tablet in FaSSGF-V2 is incomplete and
conversion to DH seems to occur. Differences between DB and DM in dissolution in the small intestine are
overestimated in the absence of physiological solubilizers. Using the in vitro data and previously described
modelling procedures, the cumulative doxazosin profile in plasma was simulated and the 0–2 h profile was used
for evaluating early exposure. Individual cumulative doxazosin profiles in plasma, after single DM tablet
administrations to 24 adults in fasting state, were constructed from corresponding actual plasma profiles.
Compared with in vitro DM data in aqueous buffers, DM data in biorelevant media led to better prediction of
early exposure. Based on intersubject variability in early exposure after DM administration and simulated
profiles, the administered phase, DB or DM, does not have a significant impact on early exposure in fasting
state. Early exposure in dogs (evaluated based on partial AUCs) was significantly higher after administration of
DM to dogs. Therefore, dog is not a good model for predicting differences between DB or DM in the fasted
state, but it may be a good model for predicting food effects and differences between DB and DM in the fed
state.

Abstract (croatian)

Glavni ciljevi ovog rada bili su istražiti da li postoje razlike u apsorpciji između lipofilne slabe baze doksazosina
(DB) i njegove mesilatne soli (DM), procijeniti sposobnost predviđanja tih razlika kod ljudi temljem in vitro
podataka, te in vivo podataka dobivenih farmakokinetskom studijom na psima. Obzirom da baze i nehidrokloridne
soli mogu prelaziti u hidrokloridne soli u kiselom mediju želuca, pored DB i DM pripremljena je,
karakterizirana i in vitro ispitana i hidrokloridna sol doksazosina (DH). Topljivost pripremljenih supstancija
ispitana je in vitro u različitim medijima metodom zasićene otopine. Brzina oslobađanja ispitana je u
jednostavnim vodenim puferima kao i biorelevantnim medijima koji simuliraju želučane i crijevne tekućine sa i
bez hrane.
Farmakokinetičke studije na psima napravljene su sa DB i DM 2 mg tabletama, sa i bez hrane, dok su rezultati
studije na zdravim dobrovoljcima nakon primjene 2 mg DM tableta bez hrane bile raspoložive iz prijašnje
Plivine studije. Analitička metoda za određivanje doksazosina u psećoj plazmi razvijena je i validirana koristeći
pseću plazmu prikupljenu u studiji s hranom, s obzirom da se u tom slučaju očekuju niže koncentracije lijeka te
veći broj interferirajućih spojeva u plazmi koji bi mogli narušavati specifičnost bioanalitičke metode.
Rezultati in vitro ispitivanja pokazuju da je topljivost DB i DM u humanom želučanom soku moguće bolje
predvidjeti koristeći biorelevantni medij (FaSSGF-V2) nego razrijeđenu kiselinu HClpH1.8. Također je pokazano
da je brzina oslobađanja doksazosina iz DB i DM tableta puno brža u HClpH1.6 nego u FaSSGF-V2. Nepotpuno
oslobađanje aktivne supstancije iz DB tableta u FaSSGF-V2 ukazuje na prelazak DB u DH. Rezultati također
pokazuju da su u odsustvu fizioloških solubilizatora, razlike u brzini oslobađanja doksazosina iz DB i DM
tableta u tankom crijevu precijenjene.
Moguće razlike u apsorpciji između DB i DM procijenjene su mjerenjem rane izloženosti, tj. brzine apsorpcije
0–2 h nakon primjene lijeka. Koristeći in vitro podatke, prosječnu bioraspoloživost nakon oralne primjene,
enterohepatičku cirkulaciju doksazosina kod ljudi, te prethodno objavljene parametre in silico modeliranja,
simuliran je kumulativni profil doksazosina u plazmi za DB i DM. Pojedinačni kumulativni profili doksazosina u
plazmi nakon primjene jediničnih 2 mg doza DM tableta u 24 zdrava dobrovoljca, konstruirani su iz
pripadajućih profila u plazmi. Rezultati pokazuju da u slučaju DM tableta, in vitro podaci u biorelevantnim
medijima bolje predviđaju ranu izloženost nego podaci u jednostavnim puferima.
Uzevši u obzir varijabilnost u ranoj izloženosti među pojedincima nakon primjene DM tableta te simulirane
profile za DB i DM, dolazi se do zaključka da vrsta administrirane supstancije (DB ili DM) nema značajnog
utjecaja na ranu izloženost kod ljudi. U studiji s psima se pokazalo da je rana izloženost kod DM bila značajno
viša nego kod DB što upućuje na zaključak da psi nisu prikladan model za procjenu razlika u brzini apsorpcije
između DB i DM kod primjene lijeka bez hrane, no mogli bi biti koristan model za predviđanje utjecaja hrane
kao i razlika između DB i DM nakon primjene lijeka s hranom.

• Keywords: doxazosin base; doxazosin salts; absorption; early exposure; solubility; dissolution; dogs; humans
• Keywords (croatian): doksazosin baza; soli doksazosina; apsorpcija; topljivost; brzina oslobađanja; psi; ljudi
• Language: english
• URN:NBN: urn:nbn:hr:163:524827
• Study programme: Title: Pharmacy and biochemistry; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor znanosti (doktor znanosti)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2016-11-16 12:33:32