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Formulation and Delivery - Chemical

(T1330-09-60) Use of PBBM-PBPK to Predict Mesalamine Delayed-Release Oral Drug Products Performance in Both Healthy and Disease Physiologies

Tuesday, November 11, 2025
1:30 PM - 2:30 PM CT
Purpose: Mesalamine (5-aminosalicylic acid (5-ASA)) is an anti-inflammatory drug indicated for the treatment of ulcerative colitis (UC) and Crohn’s disease (CD). 5-ASA acts locally in the intestines (1) and is primarily metabolized to the N-acetyl metabolite (N-Ac-5-ASA) by N-acetyltransferase 1 (NAT1) in the intestinal wall and liver. The efficacy of 5-ASA treatment can be optimized by using modified release formulations, which maximizes the local drug concentration at the site of inflammation (2). Asacol® and Mesasal® are examples of commercially available delayed-release 5-ASA formulations. (3). Predicting the in vivo behavior of such formulations can be challenging since many factors other than lumen pH play a role (1). This study aims to develop an oral absorption physiologically based pharmacokinetic (PBPK)/physiologically based biopharmaceutics model (PBBM) for 5-ASA and N-Ac-5-ASA, to predict the in vivo exposure of 5-ASA and N-Ac-5-ASA from Asacol® in healthy subjects and Mesasal® in healthy and UC or CD patients.

Methods: PBPK models for 5-ASA and N-Ac-5-ASA were built using GastroPlus® v.9.8.2 (beta version including the extended ACAT model and UC and CD physiologies). All tissues were modeled as perfusion-limited tissues and the tissue/plasma partition coefficients were calculated using the default Lukacova method for both parent drug and its metabolite. Physicochemical properties were either obtained from literature (4,5); or predicted from drug chemical structure using the ADMET Predictor® (v.10.4). To the best of our knowledge, in vitro metabolism data for 5-ASA are not reported. Hence, the in vitro Michaelis constant (Km) for an analogue (para-aminobenzoic acid) (6) was used as a surrogate and converted to an in vivo Km for NAT1. The maximum metabolism rate (Vmax) for NAT1 was then optimized using intravenous (IV) (7–9) and immediate-release oral (PO) pharmacokinetic (PK) data (8,10). The 5-ASA renal filtration clearance was defined as fraction unbound x glomerular filtration rate. The metabolite N-Ac-5-ASA is primarily excreted via renal secretion (9). Since Asacol® and Mesasal® release 5-ASA in the late parts of the GI tract, an extended GI absorption model was selected (including transverse, descending and sigmoid colon, and rectum). Asacol® dissolution profile was measured in vitro in fasted state simulated colonic fluid (FaSSCoF) and an in vitro-in vivo relationship (IVIVR) was explored with the available data (11,12). The in vivo dissolution was mechanistically deconvoluted from the plasma concentration profile after administration of 800 mg Asacol® (11). This profile was then correlated with FaSSCoF in vitro dissolution to establish a preliminary second order IVIVR (Figure 2). The IVIVR was used to scale the FaSSCoF in vitro dissolution which was used as a direct input in the model (13). Mesasal® dissolution profile in simulated intestinal fluid (SIFsp pH 6.8) was obtained from the literature (13). Due to sparse in vitro sampling and very fast dissolution profile, it was not possible to establish an IVIVR for Mesasal®. Rather, the in vivo dissolution deconvoluted from the plasma concentration profile in healthy subjects was used to model Mesasal® administration to healthy subjects and patients (14).

Results: The developed PBPK model for 5-ASA and N-Ac-5-ASA adequately described the plasma PK profile following IV and immediate-release PO in healthy subjects, as shown in Figure 1. The validated PBPK models were used to predict the plasma PK profile of 5-ASA and N-Ac-5-ASA following Asacol® and Mesasal® administration. For Asacol®, the direct use of FaSSCoF in vitro dissolution data resulted in overprediction of PK profiles (AUC and Cmax fold errors 2.63 and 2.15, respectively). The scaled dissolution profile via IVIVR resulted in reasonable PK profile prediction as shown in Figure 3. Likewise, for Mesasal®, the direct use of SIFsp in vitro dissolution data resulted in overprediction of PK profiles (AUC and Cmax fold errors 3.2 and 3.42, respectively). The healthy subject prediction using the deconvoluted in vivo dissolution profile is shown in Figure 3. Disease physiologies were generated to account for blood flow, stomach pH and intestine transit time differences between healthy subjects and patients. Since the NAT1 expression in disease condition is not known, the same expression level as in healthy was assumed. The developed PBBM-PBPK model for CD adequately described the plasma PK profile following administration of Mesasal® in CD patients (Figure 3). All subjects in the UC groups were in remission, and using the UC gut physiology resulted in an overall overprediction (data not shown). Using healthy gut physiology adequately described the plasma PK profile in UC patients (Figure 3).

Conclusion: The developed PBBM-PBPK models resulted in reasonable prediction of 5-ASA and N-Ac-5-ASA PK profiles from the different clinical PK studies. The in vivo release for both Asacol® and Mesasal® was lower than the in vitro dissolution data. This highlights the need for more biopredictive dissolution methods. The PBBM-PBPK approach presented herein can be used for assessing the biorelevance of different in vitro dissolution methods for delayed-release formulations and can serve as an aid in new and generic drug development.

References: 1. Garbacz G, Rappen GM, Koziolek M, Weitschies W. Dissolution of mesalazine modified release tablets under standard and bio-relevant test conditions. Journal of Pharmacy and Pharmacology. 2015 Feb 1;67(2):199–208.
2. Hausmann M, Paul G, Menzel K, Brunner-Ploss R, Falk W, Schölmerich J, et al. NAT1 Genotypes Do not Predict Response to Mesalamine in Patients with Ulcerative Colitis. Z Gastroenterol. 2008 Mar;46(3):259–65.
3. Sandborn WJ, Hanauer SB. The pharmacokinetic profiles of oral mesalazine formulations and mesalazine pro‐drugs used in the management of ulcerative colitis. Aliment Pharmacol Ther. 2003 Jan 19;17(1):29–42.
4. French DL, Mauger JW. Evaluation of the physicochemical properties and dissolution characteristics of mesalamine: relevance to controlled intestinal drug delivery. Pharm Res. 1993;10(9):1285–90.
5. Jung YJ, Lee JS, Kim HH, Kim YM, Han SK. Synthesis and evaluation of 5-aminosalicyl-glycine as a potential colon-specific prodrug of 5-aminosalicylic acid. Arch Pharm Res. 1998 Apr;21(2):174–8.
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8. Myers B, Evans DN, Rhodes J, Evans BK, Hughes BR, Lee MG, et al. Metabolism and urinary excretion of 5-amino salicylic acid in healthy volunteers when given intravenously or released for absorption at different sites in the gastrointestinal tract. Gut. 1987 Feb 1;28(2):196–200.
9. Vree TB, Dammers E, Exler PS, Sorgel F, Maes RAA. Saturable Active Tubular Reabsorption in the Renal Clearance of Mesalazine in Human Volunteers. Clin Drug Investig. 2000 Jul;20(1):35–42.
10. Yu DK, Elvin AT, Morrill B, Eichmeier LS, Lanman RC, Lanman MB, et al. Effect of food coadministration on 5-aminosalicylic acid oral suspension bioavailability. Clin Pharmacol Ther. 1990 Jul;48(1):26–33.
11. Sandborn WJ, Hanauer SB, Buch A. Comparative pharmacokinetics of equimolar doses of 5‐aminosalicylate administered as oral mesalamine (Asacol) and balsalazide: a randomized, single‐dose, crossover study in healthy volunteers 1. Aliment Pharmacol Ther. 2004 May 4;19(10):1089–98.
12. NDA 204-412 (eCTD 0017).
13. Klein S, Rudolph MW, Dressman JB. Drug Release Characteristics of Different Mesalazine Products Using USP Apparatus 3 to Simulate Passage Through the GI Tract. Dissolut Technol. 2002;9(4):6–12.
14. Norlander B, Gotthard R, Ström M. Pharmacokinetics of a 5‐aminosalicylic acid enteric‐coated tablet in patients with Crohn’s disease or ulcerative colitis and in healthy volunteers. Aliment Pharmacol Ther. 1990 Oct 31;4(5):497–505.

Acknowledgements: This abstract was supported by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award U01FD007660 totalling $484,699 with 100 percent funded by FDA/HHS. The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement, by FDA/HHS, or the U.S. Government. This abstract reflects the views of the author and should not be construed to represent FDA’s views or policies.

Prediction of mean systemic 5-ASA and metabolite N-Ac-ASA concentrations in healthy subjects after intravenous (IV) administration and immediate-release oral (PO) administration

In vitro-in vivo relationship between deconvoluted in vivo dissolution and in vitro dissolution in fasted state simulated colonic fluid (FaSSCoF) for Asacol® 800mg administration (11).

Prediction of mean systemic 5-ASA and metabolite N-Ac-ASA concentrations in healthy subjects after Asacol® administration and Mesasal® in healthy volunteers, UC and CD patients.