Li et al., 2018Li Y, Sun L, Lu C, Gong Y, Li M, Sun S. Promising antifungal targets against Candida albicans based on ion homeostasis. Front Cell Infect Microbiol. 2018;8:286.
|
PK-SIM |
VRC; Oral |
TDI |
Healthy Volunters |
m.d. |
VRC causes TDI of CYP3A4; 200 mg BID is sufcient for CYP2C19 intermediate metabolizers to reach the tentative therapeutic range while 400 mg BID more suitable for rapid metabolizers. |
Geometric mean error (fold 0.5 - 2.0) |
The study support TDI of CYP3A4 by VRC as an important characteristic of this drug’s PK. The PBPK model developed here could support individual dose adjustment of VRC according to genetic polymorphisms of CYP2C19, and these results are fundamental for the management of DDI's risk. |
Cristofoletti; Charoo; Dressman, 2016Cristofoletti R, Charoo NA, Dressman JB. Exploratory investigation of the limiting steps of oral absorption of fluconazole and ketoconazole in children using an in silico pediatric absorption model. J Pharm Sci. 2016;105(9):2794–2803.
|
SIMCYP |
FLU; Oral |
Intraspecie (from adults to chidren) |
Healthy volunters |
s.d. |
The absortion of FLU in fasted condition within the terapeutic range is dose indepent. The most absortion area is jejuno and the reduce of this surface area in children does not affect the absortion of FLU. Its administration in children is not solubility limited. |
n.a. |
The study corroborates to the development of models to predict diferences in absortion between children and adults after oral drug administration. |
Hens et al., 2018Hens B, Talattof A, Paixão P, Bermejo M, Tsume Y, Löbenberg R, et al. Measuring the impact of gastrointestinal variables on the systemic outcome of two suspensions of posaconazole by a PBPK model. AAPS J. 2018;20(3):57.
|
SIMCYP |
POSA; Oral |
Absortion model |
Healthy Volunters |
s.d. |
Acid suspension overpredicted the simulated concentrations over the observed concentration in early times. The amount of dissolved POSA in the stomach is crucial for the amount of POSA that will be absorbed. The fast gastric emptying rate (0.175 h) remained unchanged during these simulations, the effect of SITT on systemic drug exposure was more visible after the absorption phase. |
5% percentile and 95% percentile |
The study evaluated the impact of these GI variables on the systemic outcome of a 40 mg acidic (pH 1.6; 70% predissolved) and a 40- mg neutral (pH 7.1; 2.3% predissolved) suspension. It was clearly observed that gastric/duodenal pH and gastric emptying are the most sensitive parameters that may cause variability in systemic outcome of the drug, for both suspensions. |
Zhao et al., 2018Zhao HZ, Wang RY, Wang X, Jiang YK, Zhou LH, Cheng JH, et al. High dose fluconazole in salvage therapy for HIV-uninfected cryptococcal meningitis. BMC Infect Dis. 2018;12;18(1):643.
|
SIMCYP |
FLU;
i.v
|
Interspecie |
Neonates |
s.d. |
From juvenile mice to neonates, a correction factor of maximum lifespan potential should be used for extrapolation, while a “renal factor” taking into account renal maturation was required for successful bridging based on adult and in vitro-in silico data. Simulations results demonstrated that the predicted drug exposure based on bridging approach was comparable to the observed value in neonates. The prediction errors were -2.2%, +10.1% and -4.6% for juvenile mice, adults and in vitro-in silico data, respectively. |
Prediction error (PE) |
The results approach to predict the PK of FLU in neonates from juvenile mice, adults and in vitro-in silico data. Our results firstly support the feasibility of PK bridging approach in neonates. |
Watt et al., 2018Watt KM, Cohen-Wolkowiez M, Barrett JS, Zhao P, Brouwer KLR, Edginton AN. Physiologically Based Pharmacokinetic Approach to Determine Dosing on Extracorporeal Life Support: Fluconazole in Children on ECMO. Citation: CPT Pharmacometrics Syst. Pharmacol. 2018;7, 629–637.
|
PK-SIM |
FLU; oral |
Intraspecie (from adults to children) |
Healthy voluters and patients with ECMO |
s.d. |
The pediatric PBPK model only captured 74% of the observed data for critically ill infants, but this was expected because the model was based on healthy infants. Critically ill children have more variability in exposure due to disease. By accounting for the developmental changes in body size and physiology as children age, the current ECMO PBPK model was able to predict the optimal loading dose for each age group. However, the optimal regimen may be too complicated for clinical implementation. |
Fold error 0.7-1.3 |
The study described in this study should provide an approach to dose determination in this difficult to study population that provides needed flexibility to account for different and evolving extracorporeal circuit components and reduces the number of children enrolled in clinical trials. |
Frechen et al., 2013Frechen S, Junge L, Saari TI, Suleiman AA, Rokitta D, Neuvonen PJ, et al. A semiphysiological population pharmacokinetic model for dynamic inhibition of liver and gut wall cytochrome P450 3a By Voriconazole. Clin Pharmacokinet. 2013;52(9):763–781.
|
NONMEN |
VRC; i.v and oral |
DDI |
Healthy Volunters |
m.d. |
Identification of an apparent sustained inhibitory effect by VRC due to a proposed quasi accumulation at the enzyme site, a significantly reduced inhibitory potency of intravenous VRC for oral substrates. |
90% of CI's |
The proposed model focused on in vivo clinical trials is a powerful tool for maximizing knowledge obtained from clinical DDI studies and serves as a complementary instrument in addition to mechanistically test the classical NCA and specifically in vitro-based (physiological-based) simulation models the magnitude of DDIs. |
Hens et al., 2017Hens B, Pathak SM, Mitra A, Patel N, Liu B, Patel S, et al. In silico modeling approach for the evaluation of gastrointestinal dissolution, supersaturation, and precipitation of posaconazole. Mol Pharm. 2017;14(12):4321-4333.
|
SIMCYP |
POSA; oral |
ADAM |
Healthy Volunters |
s.d. |
For the first time, this research demonstrated predictive in silico simulations of GI dissolution, supersaturation, and precipitation for a weakly simple compound, told in part by modeling of in vitro dissolution studies and validated with clinical measurements in both GI fluids and plasma. |
n.a. |
This research illustrates the predictive capacity of PBPK modeling in evaluating the effect of formulation pH on systemic exposure for two suspensions of a dose of POSA. |
Liu et al., 2017Liu B, Crewe HK, Ozdemir M, Rowland Yeo K, Tucker G, Rostami-Hodjegan A. The absorption kinetics of ketoconazole plays a major role in explaining the reported variability in the level of interaction with midazolam: Interplay between formulation and inhibition of gut wall and liver metabolism. Biopharm Drug Dispos. 2017;38(3):260-270.
|
SIMCYP |
KETO; oral |
ADAM/ IVIVE |
Clinical trials |
s.d. |
Established KTZ PBPK model successfully identified the effect of supersaturation and precipitation on the systemic plasma concentration profiles of KETO. |
n.a. |
These findings show that IVIVE can be used in biopharmaceutical experiments to understand and gain trust in the accuracy of the input parameters and mechanistic models used for in vivo mechanistic oral absorption simulations, thus enhancing the prediction efficiency of PBPK models. |
Ruff; Fiolka; Kostewicz, 2017Ruff A, Fiolka T, Kostewicz ES. Prediction of Ketoconazole absorption using an updated in vitro transfer model coupled to physiologically based pharmacokinetic modelling. Eur J Pharm Sci. 2017;100:42-55.
|
STELLA |
KETO; oral |
ADAM/ IVIVE |
Clinical trials |
s.d. |
Oral solution plasma profile simulations with in-vitro transition experimental results were conducted using the Nizoral® tablets predissolved. In the case of an oral solution, no disintegration must be assumed and gastric emptying is the most critical stage in bringing the dissolved substance to the absorption site. |
ANOVA |
The proposed standard transfer models therefore provided the most precise simulation of the observed profile and support the hypothesis of making the in vitro sample more physiologically important when coupled with PBPK. |
Silva et al., 2018Silva DA, Duque MD, Davies NM, Löbenberg R, Ferraz HG. Application of in silico tools in clinical practice using ketoconazole as a model drug. J Pharm Pharm Sci. 2018;21(1s):242s-253s.
|
GASTROPLUS |
KETO; oral |
ADAM |
Patients with Hypochlorhydria |
s.d. |
The developed model accurately predicted the impact of increased pH and beverage co-administration on drug dissolution and absorption, confirming that complete gastric dissolution is required. |
Two-fold error |
Reliable models of PBPK can be used to forecast future pharmacokinetic pitfall, opening up additional approaches for researching clinical practice dosing strategies. |
Johnson et al., 2018Johnson TN, Bonner JJ, Tucker GT, Turner DB, Jamei M. Development and applications of a physiologically-based model of paediatric oral drug absorption. Eur J Pharm Sci. 2018; 115:57-67.
|
SIMCYP |
KETO; oral |
ADAM |
Pediatrics |
s.d. |
The tmax of KETO was estimated to be around 1h in both neonates and adults, but the former had a higher fa rating. |
** |
While some performance testing was carried out, the components of the model obviously need to be extended as new research on GI tract ontogeny is available and evaluated against further in vivo proof of real drug absorption age-related results. |
Qi et al., 2017Qi F, Zhu L, Li N, Ge T, Xu G, Liao S. Influence of different proton pump inhibitors on the pharmacokinetics of voriconazole. Int J Antimicrob Agents. 2017;49(4):403-409.
|
SIMCYP |
VRC; oral |
DDI |
Healthy Volunters |
s.d. |
The findings showed that the plasma concentration–time profiles of VRC and PPIs simulated by the PBPK model were compatible with the observed profiles. Furthermore, the DDI simulations indicated that VRC PK values improved to varying degrees when paired with different PPIs. |
AFE < 2.0 |
However, due to the medicinal concentration spectrum, VRC dose modification is inappropriate regardless of which PPI was co-administered. |
Zane; Thakker, 2014Zane NR, Thakker DR. A physiologically based pharmacokinetic model for voriconazole disposition predicts intestinal first-pass metabolism in children. Clin Pharmacokinet. 2014;53(12):1171-82.
|
SIMCYP |
VRC; i.v. |
Intraspecie (from adults to children) |
Healthy children and adults |
s.d. |
The estimation of oral bioavailability increased significantly after integrating intestinal first-pass metabolism into the model, indicating that VRC is subject to intestinal first-pass metabolism in children but not in adults. |
20% prediction error of the observed values |
The PBPK method employed in this research provides a mechanistic explanation for the discrepancies in bioavailability between adults and infants. This will be the first instance of unequal first-pass metabolism in children and adults, if verified. |