International Journal of Drug Delivery Technology
Volume 14, Issue 1

Assessment of Inter-Individual Pharmacokinetic Variability of Voriconazole Based on Bile Salt Disparities using POP-PK Modeling

Priya Sharma1,2, Tanveer Naved1, Arti R Thakkar1*

1Amity Institute of Pharmacy, Amity University, Noida, Uttar Pradesh, India.

2School of Pharmacy, Sharda University, Greater Noida, Uttar Pradesh, India. 

Received: 15th September, 2023; Revised: 01st January, 2024; Accepted: 17th February, 2024; Available Online: 25th March, 2024

ABSTRACT

Background and Objectives: Voriconazole is a powerful biopharmaceutics classification system (BCS) class II antifungal agent with vast inter-individual pharmacokinetic variability. Bile salts have recently emerged as potential contributors to such variations. Based on population PK modeling and in-vitro biorelevant dissolution investigations, the current study intends to evaluate the inter-individual variability of voriconazole in pediatrics.

Methods: All models were developed using PK-Sim software. A simulated population consisting of 100 pediatric individuals was established following the baseline model development. Further, experimentally obtained in-vitro dissolution data of voriconazole based on the bile salt differences representing different pediatric age groups were incorporated into a qualified pediatric model. Simulated plasma concentration-time profiles were then evaluated by comparing model-predicted parameters with that of the baseline model to draw inferences.

Result: Each model was created and validated successfully. The pediatric subjects were shown to have larger inter-individual variability than adult subjects. Additionally, simulations based on individual parameter estimations from the final model showed that after administering a 4 mg/kg peroral dose of voriconazole, the anticipated Cmax values of the adult model were within a two-fold range compared to that of the pediatric model. However, upon comparison, the model-predicted population pk profiles of children, infants, and neonates showed minimal variations in the Cmax values.

Conclusion: In pediatrics, voriconazole inter-individual variability was significantly influenced by the concentration of gut bile salts. Furthermore, the present research can be carried forward along with population PK modeling and sufficient clinical data for dose recommendations in special populations as well as in diseased conditions.

Keywords: Bile salts, Biorelevant, In-vitro dissolution, Inter-individual variability, Pediatric population, PBPK modeling, voriconazole.

International Journal of Drug Delivery Technology (2024); DOI: 10.25258/ijddt.14.1.09

How to cite this article: Sharma P, Naved T, Thakkar AR. Assessment of Inter-Individual Pharmacokinetic Variability of Voriconazole Based on Bile Salt Disparities using POP-PK Modeling. International Journal of Drug Delivery Technology. 2024;14(1):50-54.

REFERENCES

  1. Cohen-Wolkowiez M, Moran C, Benjamin Jr DK, Smith PB. Pediatric antifungal agents. Current opinion in infectious 2009; 22(6):553. DOI: 10.1097/QCO.0b013e3283321ccc.
  2. Pascual A, Calandra T, Bolay S, Buclin T, Bille J, Marchetti Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clinical infectious diseases. 2008; 46(2):201-11. DOI: 10.1086/524669
  3. Jasim NO. A Possible Warning for COVID-19 Patients on Complications of Fungal Infection: A review. International Journal of Pharmaceutical Quality Assurance. 2021:84-7. DOI:10.25258/ijpqa.12.2.12
  4. Zhang P, Jiang EL, Yang DL, Yan ZS, Huang Y, Wei JL, Wang M, Ma QL, Liu QG, Zou DH, He Risk factors and prognosis of invasive fungal infections in allogeneic stem cell transplantation recipients: a single‐institution experience. Transplant Infectious Disease. 2010; (4):316-21. DOI:10.1111/j.1399-3062.2010.00497.x
  5. Zhang Y, Zhao S, Wang C, Zhou P, Zhai S. Application of a physiologically based pharmacokinetic model to characterize time-dependent metabolism of voriconazole in children and support dose optimization. Frontiers in Pharmacology. 2021; 12:636097. DOI:10.3389/fphar.2021.636097.
  6. Zane NR, Thakker A physiologically based pharmacokinetic model for voriconazole disposition predicts intestinal first- pass metabolism in children. Clinical pharmacokinetics. 2014; 53:1171-82. DOI:10.1007/s40262-014-0181-y.
  7. Schulz J, Kluwe F, Mikus G, Michelet R, Kloft Novel insights into the complex pharmacokinetics of voriconazole: a review of its metabolism. Drug Metabolism Reviews. 2019; 51(3):247-65. DOI:10.1080/03602532.2019.1632888.
  8. Spriet I, Cosaert K, Renard M, Uyttebroeck A, Meyts I, Proesmans M, Meyfroidt G, de Hoon J, Verbesselt R, Willems Voriconazole plasma levels in children are highly variable. European journal of clinical microbiology & infectious diseases. 2011;30:283-7. DOI: 10.1007/s10096-010-1079-8
  9. Ascioglu S, Rex JH, De Pauw B, Bennett JE, Bille J, Crokaert F, Denning DW, Donnelly JP, Edwards JE, Erjavec Z, Fiere Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clinical infectious diseases. 2003;5(1):10-6. DOI:10.1086/323335.
  10. Hu R, Jiang XY, Wu Y. Risk factors for invasive pulmonary fungal infection in patients with hematological malignancies not receiving hematopoietic stem cell transplant. Neoplasma. 2012; 59(6):669. DOI:10.4149/neo_2012_085.
  11. Islam N, Gladki Dry powder inhalers (DPIs)—a review of device reliability and innovation. International journal of pharmaceutics. 2008; 360(1-2):1-1. DOI: doi.org/ 10.1016/j. ijpharm.2008.04.044.
  12. Liu P, Mould DR. Population pharmacokinetic analysis of voriconazole and anidulafungin in adult patients with invasive aspergillosis. Antimicrobial agents and chemotherapy. 2014; 58(8):4718-26. DOI:10.1128/AAC.02808-13
  13. VFEND® I.V. (voriconazole) for Injection VFEND® Tablets (voriconazole) VFEND® (voriconazole) for Oral Suspension,VFEND - fda.gov https://www.accessdata.fda.gov
  14. Hu L, Huang Q. Population pharmacokinetics of voriconazole and CYP2C19 phenotype for dose optimization in hematological patients with invasive fungal infections. DOI: https://doi. org/10.21203/rs.3.rs-2270024/v1
  15. Dolton MJ, Ray JE, Chen SC, Ng K, Pont LG, McLachlan AJ. Multicenter study of voriconazole pharmacokinetics and therapeutic drug monitoring. Antimicrobial agents and 2012; 56(9):4793-9. DOI: https://doi.org/10.1128/ aac.00626-12
  16. Johnson HJ, Han K, Capitano B, Blisard D, Husain S, Linden PK, Marcos A, Kwak EJ, Potoski B, Paterson DL, Romkes M. Voriconazole pharmacokinetics in liver transplant recipients. Antimicrobial agents and 2010 ;54(2):852-9. DOI: https://doi.org/10.1128/aac.00429-09
  17. Wang T, Yan M, Tang D, Xue L, Zhang T, Dong Y, Zhu L, Wang X, Dong Therapeutic drug monitoring and safety of voriconazole therapy in patients with Child–Pugh class B and C cirrhosis: a multicenter study. International Journal of Infectious Diseases. 2018; 72:49-54. DOI: https://doi.org/10.1016/j.ijid.2018.05.009.
  18. Miyakis S, Van Hal SJ, Ray J, Marriott D. Voriconazole concentrations and outcome of invasive fungal infections. Clinical Microbiology and Infection. 2010; 16(7):927-33. DOI:10.1111/j.1469-0691.2009.02990.x.
  19. Miyakis S, Van Hal SJ, Solvag CJ, Ray J, Marriott D. Clinician ordering practices for voriconazole therapeutic drug monitoring: experiences of a referral Therapeutic drug monitoring. 2010; 32(5):661-4. DOI:10.1097/FTD.0b013e3181ea3de6.
  20. Trifilio SM, Yarnold PR, Scheetz MH, Pi J, Pennick G, Mehta Serial plasma voriconazole concentrations after allogeneic hematopoietic stem cell transplantation. Antimicrobial agents and chemotherapy. 2009; 53(5):1793-6. DOI:10.1128/AAC.01316-08.
  21. Schulz J, Michelet R, Zeitlinger M, Mikus G, Kloft C. Microdialysis of drug and drug metabolite: a comprehensive in vitro analysis for voriconazole and voriconazole N-oxide. Pharmaceutical Research. 2022; 39(11):2991-3003. DOI: https:// doi.org/10.1007/s11095-022-03292-0
  22. Yanni SB, Annaert PP, Augustijns P, Ibrahim JG, Benjamin DK, Thakker DR. In vitro hepatic metabolism explains higher clearance of voriconazole in children versus adults: role of CYP2C19 and f lavin-containing monooxygenase 3. Drug Metabolism and 2010; 38(1):25-31. DOI: https://doi. org/10.1124/dmd.109.029769
  23. Mithani SD, Bakatselou V, TenHoor CN, Dressman JB. Estimation of the increase in solubility of drugs as a function of bile salt Pharmaceutical research. 1996; 13:163-7. DOI: 10.1023/A:1016062224568
  24. Guimarães M, Maharaj A, Edginton A, Vertzoni M, Fotaki N. Understanding the Impact of Age-Related Changes in Pediatric GI Solubility by Multivariate Data Analysis. Pharmaceutics. 2022; 14(2):356. DOI: https://doi.org/10.3390/pharmaceutics14020356
  25. Galia E, Nicolaides E, Hörter D, Löbenberg R, Reppas C, Dressman Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs. Pharmaceutical research. 1998; 15:698-705. DOI: 10.1023/A:1011910801212
  26. Jantratid E, Janssen N, Reppas C, Dressman JB. Dissolution media simulating conditions in the proximal human gastrointestinal tract: an update. Pharmaceutical research. 2008; 25:1663-76. DOI: 10.1007/s11095-008-9569-4
  27. Shono Y, Jantratid E, Janssen N, Kesisoglou F, Mao Y, Vertzoni M, Reppas C, Dressman JB. Prediction of food effects on the absorption of celecoxib based on biorelevant dissolution testing coupled with physiologically based pharmacokinetic modeling. European Journal of Pharmaceutics and Biopharmaceutics. 2009; 73(1):107-14. DOI: https://doi.org/10.1016/j.ejpb.2009.05.009
  28. Dressman JB, Reppas C. In vitro–in vivo correlations for lipophilic, poorly water-soluble drugs. European journal of pharmaceutical sciences. 2000; 11:S73-80. DOI: https://doi. org/10.1016/S0928-0987(00)00181-0
  29. Kaye JL. Review of paediatric gastrointestinal physiology data relevant to oral drug delivery. International journal of clinical pharmacy. 2011 Feb;33:20-4. Doi: 1007/s11096-010-9455-0
  30. Mooij MG, de Koning BA, Huijsman ML, de Wildt SN. Ontogeny of oral drug absorption processes in children. Expert opinion on drug metabolism & toxicology. 2012; 8(10):1293-303. DOI: https://doi.org/10.1517/17425255.2012.698261
  31. Geigy Scientific Tables. Edn 7, Geigy Pharmaceuticals, New York,1974.
  32. Selen A, Dickinson PA, Müllertz A, Crison JR, Mistry HB, Cruañes MT, Martinez MN, Lennernäs H, Wigal TL, Swinney DC, Polli JE. The biopharmaceutics risk assessment roadmap for optimizing clinical drug product performance. Journal of Pharmaceutical 2014; 103(11):3377-97. DOI:10.1002/ jps.24162.
  33. Kaur N, Narang A, Bansal AK. Use of biorelevant dissolution and PBPK modeling to predict oral drug absorption. European Journal of Pharmaceutics and 2018; 129:222-DOI:10.1016/j.ejpb.2018.05.024.18.
  34. Sharma P, Rana RK, Thakkar AR. Evaluation of the impact of age-specific bile salt differences on the dissolution behavior of voriconazole using biorelevant media. Journal of Research in Pharmacy 2023 (Accepted manuscript, Manuscript Id- MPJ- 11341).
  35. Maharaj A R, Edginton A Physiologically based pharmacokinetic modeling and simulation in pediatric drug development. CPT: pharmacometrics & systems pharmacology. 2014; 3(11):1-3. DOI:10.1038/psp.2014.45.
  36. Indian Pharmacopoeia (I.P), 2007, On behalf of the government of India ministry of health and family welfare, Indian Pharmacopoeia Commission Ghaziabad, ISBN 81-903436-0-3, pp-241-242.
  37. Maharaj AR, Edginton AN, Fotaki Assessment of age-related changes in pediatric gastrointestinal solubility. Pharmaceutical research. 2016; 33:52-71. DOI: 10.1007/s11095-015-1762-7
  38. Van Den Abeele J, Rayyan M, Hoffman I, Van de Vijver E, Zhu W, Augustijns P. Gastric fluid composition in a paediatric population: age-dependent changes relevant for gastrointestinal drug European Journal of Pharmaceutical Sciences. 2018; 123:301-11. DOI: https://doi.org/10.1016/j.ejps.2018.07.022
  39. Silva TV, De Barros NR, Costa-Orlandi CB, Tanaka JL, Moro LG, Pegorin GS, Oliveira KS, Mendes-Gianinni MJ, Fusco- Almeida AM, Herculano RD. Voriconazole-natural latex dressings for treating infected Candida spp. skin ulcers. Future 2020; 15(15):1439-52. DOI: https://doi.org/10.2217/ fmb-2020-0122
  40. Kambayashi A, Yasuji T, Dressman JB. Prediction of the precipitation profiles of weak base drugs in the small intestine using a simplified transfer (“dumping”) model coupled with in silico modeling and simulation approach. European Journal of Pharmaceutics and Biopharmaceutics. 2016; 103:95-103. DOI: https://doi.org/10.1016/j.ejpb.2016.03.020
  41. Sharma P, Tummala HP, Mallayasamy R, Thakkar Predicting the impact of bile salt variations on the pharmacokinetics of voriconazole using biorelevant dissolution-based PBPK modeling. Current Drug Metabolism ( communicated manuscript)
  42. Kim K, Yoon I, Chun I, Lee N, Kim T, Gwak HS. Effects of bile salts on the lovastatin pharmacokinetics following oral administration to Drug Delivery. 2011; 18(1):79-83. DOI:1 0.3109/10717544.2010.512024.
  43. Li X, Frechen S, Moj D, Lehr T, Taubert M, Hsin CH, Mikus G, Neuvonen PJ, Olkkola KT, Saari TI, Fuhr U. A physiologically based pharmacokinetic model of voriconazole integrating time- dependent inhibition of CYP3A4, genetic polymorphisms of CYP2C19 and predictions of drug–drug Interactions. Clinical 2020; 59:781-808. DOI:10.1007/s40262-019- 00856-z.
  44. Scholz I, Oberwittler H, Riedel KD, Burhenne J, Weiss J, Haefeli WE, Mikus G. Pharmacokinetics, metabolism and bioavailability of the triazole antifungal agent voriconazole in relation to CYP2C19 genotype. British journal of clinical 2009; 68(6):906-15. DOI: https://doi.org/10.1111/ j.1365-2125.2009.03534.x
  45. Chowdary KPR, Shankar RK, Chandrashekhar CH, Enhancement of dissolution rate and formulation development of voriconazole tablets by solid dispersion in combined Journal of Pharmaceutical Sciences 2014: 855-863. DOI: https:// ccde04f64eb3a86779a112984558b9da403033b1
  46. FDA Antiviral Drugs Advisory Committee briefing document for voriconazole (oral and intravenous formulations) http://www. gov/ohrms/dockets/AC/01/briefing /3792 b2_01_ Pfizer.pdf, Pfizer, 2003.
  47. Purkins L, Wood N, Greenhalgh K, Allen MJ, Oliver Voriconazole, a novel wide‐spectrum triazole: oral pharmacokinetics and safety. British Journal of Clinical Phar macolog y. 2003; 56:10 - 6 . DOI:10.1046/ j.1365 - 2125.2003.01993.x
  48. Karlsson MO, Lutsar I, Milligan Population pharmacokinetic analysis of voriconazole plasma concentration data from pediatric studies. Antimicrobial agents and chemotherapy. 2009; 53(3):935-DOI:10.1128/AAC.00751-08
  49. Sharma P, Rana RK, Thakkar AR. Evaluation of the impact of age-specific bile salt differences on the dissolution behavior of voriconazole using biorelevant media. Journal of Research in Pharmacy 2023 (Accepted manuscript)
  50. Greer Voriconazole: the newest triazole antifungal agent. InBaylor University Medical Center Proceedings 2003 Apr 1 (Vol. 16, No. 2, pp. 241-248). Taylor & Francis. DOI: 10.1080/08998280.2003.11927910.
  51. Jalundhwala F. Approaches to Development of Analytical Method for Combination Products Containing International Journal of Pharmaceutical Quality Assurance 2014; 5(1); 1-5.
  52. Mahal RK, Al-Gawhari F. Design, Development and Optimization of Solid Lipid Nanoparticles for Ocular Delivery of an Antifungal International Journal of Drug Delivery Technology. 2023;13(1):327-339. DOI: 10.25258/ijddt.13.1.54
  53. Al-Wandawy A, Zwain LA, Wali MR. Study of Antibiotic- resistant Bacteria Isolated from Children with Urinary Tract Infection. International Journal of Drug Delivery Technology. 2023;13(1):150-157. DOI: 25258/ijddt.13.1.23
  54. Fenton OS, Olafson KN, Pillai PS, Mitchell MJ, Langer R. Advances in biomaterials for drug Advanced Materials. 2018; 30(29):1705328.