The role of modeling and simulation to improve the treatment of fungal infections caused by <i>Cryptococcus</i>:  A literature review

Staudt, Keli Jaqueline; Olivo, Laura Ben; Alves, Izabel Almeida; Araújo, Bibiana Verlindo de

doi:10.1590/s2175-97902024e23446

Keli Jaqueline Staudt

Pharmaceutical Sciences Graduate Program of Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil

Laura Ben Olivo

Pharmaceutical Sciences Graduate Program of Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil

Izabel Almeida Alves

Laboratory of Pharmacokinetics and Pharmacometrics, Faculty of Pharmacy, Federal University of Bahia (UFBA), Salvador, Bahia, Brazil

Bibiana Verlindo de Araújo E-mail: bibiana.araujo@ufrgs.br

Pharmaceutical Sciences Graduate Program of Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil

* Correspondence: B. V. de Araújo. Programa de Ciências Farmacêuticas. Universidade Federal do Rio Grande do Sul. Av. Ipiranga, 2752, Porto Alegre, Rio Grande do Sul, 90610-000, Brasil. Fone: (+ 55 51) 3308-5418.

https://orcid.org/0000-0002-9706-0389

E-mail: bibiana.araujo@ufrgs.br

^*
Correspondence:

B. V. de Araújo. Programa de Ciências Farmacêuticas. Universidade Federal do Rio Grande do Sul. Av. Ipiranga, 2752, Porto Alegre, Rio Grande do Sul, 90610-000, Brasil. Fone: (+ 55 51) 3308-5418.

Ref.	Patients/animal model characteristics	Drug and Dosage regimen	Yeast and MIC	PK/PD index	Outcomes
*Wu et al.* , 2014** Wu JQ, Shao K, Wang X, Wang RY, Cao YH, Yu YQ, et al. In vitro and in vivo evidence for amphotericin B as a P-glycoprotein substrate on the blood-brain barrier. Antimicrob Agents Chemother. 2014;58(8):4464-9.	Murine with cryptococcal meningitis	3 mg/kg/d i.v. of Amp-B, 10 mg/kg i.v. of VERA and ITZ	C. neoformans (clinical isolate)	n.a.	This study demonstrated that Amp-B is probably a substrate for Pg-P and that they can increase Amp-B uptake through BBB, leading to a reduction in fungal load on the brain.
*Sudan et al.* , 2013** Sudan A, Livermore J, Howard SJ, Al-Nakeeb Z, Sharp A, Goodwin J, et al. Pharmacokinetics and pharmacodynamics of fluconazole for cryptococcal meningoencephalitis: implications for antifungal therapy and in vitro susceptibility breakpoints. Antimicrob Agents Chemother. 2013;57(6):2793-800.	Nonimmunosuppressed murine model of cryptococcal meningitis	125 and 250 mg/kg p.o. once a day for 9 days of FLU	C. neoformans (4 clinical isolates) 3; 3.33; 3.67 and 7.33 µg/mL	AUC/MIC = 389	The MIC was important to understand the exposure-response relationships, because the AUC/MIC ratio of 389 was the index mor efficient for FLU.
*Santos et al.* , 2016** Santos JRA, César IC, Costa MC, Ribeiro NQ, Holanda RA, Ramos LH, et al. Pharmacokinetics/pharmacodynamic correlations of fluconazole in murine model of cryptococcosis. Eur J Pharm Sci. 2016;92:235-43.	Murine model of cryptococcosis	75 mg/kg p.o. daily of FLU	C. gattii L27/01= 16μg/mL and C. gattii L27/01 _F = 128 μg/mL	AUC/MIC	The maximum concentration of FLU in the brain was lower than the MIC for both strains.
*Alhadab et al.* , 2019** Alhadab AA, Rhein J, Tugume L, Musubire A, Williams DA, Abassi M, et al. Pharmacokinetics-Pharmacodynamics Of Sertraline As An Antifungal In Hiv-Infected Ugandans With Cryptococcal Meningitis. J Pharmacokinet Pharmacodyn. 2019;46:565–576.	HIV-infected Ugandan patients with cryptococcal meningitis	100, 200, 300, 400 mg/day of SER; 0.7 – 1.0 mg/kg per day and 800 mg/day of FLU	Cryptococcus clinical isolates Mean 4 µg/mL (SER)	No PK/PD index correlated	They observed that the concentrations of unbound SER do not reach MIC concentrations. None of the selected PK/PD index correlated with the decrease in the log ₁₀ CFU/mL.
*Hope et al.* , 2019** Hope W, Stone NRH, Johnson A, McEntee L, Farrington N, Santoro-Castelazo A, et al. Fluconazole monotherapy is a suboptimal option for initial treatment of cryptococcal meningitis because of emergence of resistance. mBio. 2019;10(6):e02575-19.	Murine model of cryptococcal meningitis	125 and 250 mg/kg p.o once a day of FLU	C. neoformans (ATCC 208821) 4 µg/mL	f AUC/MIC = 231,4	The emergence of resistance was observed in vivo with a f AUC/MIC of 231.4.

Ref.	Patients/animal model characteristics	Drug and Dosage regimen	Pharmacokinetic parameters (median)						Outcomes
Ref.	Patients/animal model characteristics	Drug and Dosage regimen	λ	Vss	CL	AUC_0-∞	F	ppb	Outcomes
*Black et al., 2014*Black LA, Krockenberger MB, Kimble B, Govendir M. Pharmacokinetics of fluconazole following intravenous and oral administration to koalas (Phascolarctos cinereus). J Vet Pharmacol Ther. 2014;37(1):90-8.	Clinically normal koalas	10 mg/kg p.o and i.v. of FLU	4.69 h p.o. 2.25 h i.v.	0.92 L/kg i.v.	0.31 L/h/kg i.v.	22.87 µg/mLh p.o. 34.54 µg/mLh i.v.	53%	39.5%	This study demonstrated striking differences in t½, CL, Vss, F and PPB for koalas compared to other mammals.
*Wang et al., 2017*Wang W, Zheng N, Zhang J, Huang X, Yu S. Effect of Efflux Transporter inhibition on the distribution of fluconazole in the rat brain. Neurochem Res. 2017;42(8):2274-2281.	Male Sprague–Dawley rats	10 and 20 mg/kg i.v. of FLU	n.a.	n.a.	n.a.	AUC_0-300 plasma 2619 ±135 (dose 10 mg/kg); 4587 ± 207 (dose 20mg/kg) without probenecid 2975 ± 113 (dose 10 mg/kg); 5156 ± 229 (dose 20mg/kg) with probenecid AUC_0-300ECF 1587 ±110 (dose 10 mg/kg); 2853 ± 207 (dose 20mg/kg) without probenecid 2176 ± 114 (dose 10 mg/kg); 4113 ± 201 (dose 20mg/kg) with probenecid	n.a.	11.0%	The combined use of probenecid increased the penetration of FLU into the BBB, which would increase the concentration of FLU in a brain lesion without increasing the dose of FLU.
*Alves et al., 2018* Alves IA, Staudt KJ, Carreño FO, De Araujo GL, De Miranda Silva C, Rates SMK et al. Population pharmacokinetic modeling to describe the total plasma and free brain levels of fluconazole in healthy and Cryptococcus Neoformans infected rats: How does the infection impact the drug’s levels on biophase? Pharm Res. 2018;35:1–10.	Model of cryptococcal meningoencephalitis in rats	20 mg/kg i.v. of FLU	Healthy Plasma 0.11 h Brain 0.19 h Infected Plasma 0.15 h Brain 0.16 h	Healthy Plasma 0.336 L Infected Plasma 0.255 L	Healthy Plasma 0.031 L/h Infected Plasma 0.034 L/h	Healthy Plasma 220.88 µgh/mL Brain 135.50 µgh/mL Infected Plasma 183.20 µgh/mL Brain 166.68 µgh/mL	93%	90%	In infected animals the infection caused an influence on the distribution of FLU to the brain.
*Kirbs et al., 2019*Kirbs C, Kluwe F, Drescher F, Lackner E, Matzneller P, Weiss J, et al. High voriconazole target-site exposure after approved sequence dosing due to nonlinear pharmacokinetics assessed by long-term microdialysis. Eur J Pharm Sci. 2019;131:218-229.	Healthy male volunteers	i.v. infusions day 1 (6 mg/kg over 2 h) and day 2 (4 mg/kg over 1.3 h). Day 3 and 4, 200 mg every 12 h of tablets of VRC	Plasma s.d. (0-12h) 0.09; m.d. (48-60h) 0.05; m.d. (72-84h) 0.06 ISF s.d. (0-12h) 0.09; m.d. (45-60h) 0.03; m.d. (72-84h) 0.04	n.a.	Plasma m.d. (72-84h) 16.3 L/h ISF m.d. (72-84h) 14.8 L/h	Plasma s.d. (0-12h) 7.30 mgh/L; m.d. (48-60h) 14.7 mgh/L; m.d. (72-84h) 12.3 mgh/L ISF* s.d. (0-12h) 5.39 mgh/L; m.d. (48-60h) 14.7 mgh/L; m.d. (72-84h) 13.5 mg*h/L;	96%	47.1 %	In this study, a high interindividual variability was observed in the concentration-time profiles of VRC, although doses have been adapted to body weight in the first i.v. administrations.

Ref.	Patients/animal model characteristics	Yeast and MIC	Drug and Dosage regimen	Sample	Assessment of activity and MIC methods	Model	Outcomes
*Sudan et al.* , 2013** Sudan A, Livermore J, Howard SJ, Al-Nakeeb Z, Sharp A, Goodwin J, et al. Pharmacokinetics and pharmacodynamics of fluconazole for cryptococcal meningoencephalitis: implications for antifungal therapy and in vitro susceptibility breakpoints. Antimicrob Agents Chemother. 2013;57(6):2793-800.	Nonimmunosuppressed murine model of cryptococcal meningitis	C. neoformans 3; 3.33; 3.67 and 7.33 µg/mL	125 and 250 mg/kg once a day for 9 days of FLU	Plasma and cerebrum	CLSI method	5-compartment mathematical model consisting by 5 ordinary differential equations and the relationship between the AUC/MIC ratio versus decline in fungal density was modeled using the sigmoid E _max model	The mathematical model was adjusted to the PK/PD data and showed that FLU may be an inferior drug for induction therapy because many patients are unable to achieve the pharmacodynamic goal, being advised to use the highest possible dose.
*O’Connor et al.* , 2013** O’Connor L, Livermore J, Sharp AD, Goodwin J, Gregson L, Howard SJ, et al. Pharmacodynamics of liposomal amphotericin B and flucytosine for cryptococcal meningoencephalitis: safe and effective regimens for immunocompromised patients. J Infect Dis. 2013;208(2):351-61.	Murine model of cryptococcal meningoencephalitis	C. neoformans var. grubii (ATCC 208821) 1 μg/mL for LAmp-B and 0.125 μg/mL for flucytosine	LAmp-B 3, 10 and 20 mg/kg i.v. daily and flucytosine 20, 50 and 100 mg/kg/d i.v.	Plasma and cerebrum	CLSI M27-A3 method	A Greco model implemented within ADAPT 5 was used to modeled the effect of the combination of LAmp-B and flucytosine	This study demonstrated that both LAmp-B and flucytosine produced a dose-dependent reduction in fungal load. And the effect of the combination of agents on the brain was additive.
*Santos et al.* , 2016** Santos JRA, César IC, Costa MC, Ribeiro NQ, Holanda RA, Ramos LH, et al. Pharmacokinetics/pharmacodynamic correlations of fluconazole in murine model of cryptococcosis. Eur J Pharm Sci. 2016;92:235-43.	Murine model of cryptococcosis	C. gattii L27/01= 16μg/mL and C. gattii L27/01 _F = 128 μg/mL	75 mg/kg daily and of FLU 0.2 mg/kg daily of Amp-B	Serum, lungs, and brain	CLSI M27-A3 method	Modified E _max -model and sigmoid E _max model	The maximum concentration of FLU in the brain was lower than the MIC for strains. The treatment of mice infected with the resistant strain was ineffective even with the use of high doses of FLU or when testing Amp-B, confirming cross-resistance between these drugs.
*Lestner et al.* , 2017** Lestner J, McEntee L, Johnson A, Livermore J, Whalley S, Schwartz J, et al. Experimental models of short courses of liposomal amphotericin B for induction therapy for cryptococcal meningitis. Antimicrob Agents Chemother. 2017;24;61(6):e00090-17.	Murine and rabbit models of cryptococcal meningoencephalitis	C. neoformans var. grubii (ATCC 208821)	LAmp-B i.v.	Plasma and cerebrum	EUCAST and CLSI methods	Population model used PK and PD murine data with the program Pmetrics was performed using four differential equations	The rabbits study suggests that more than a single dose is needed to treat cryptococcal meningitis, whereas the study in mice may underestimate the total exposure of the drug that is necessary for fungicidal activity in humans, as they had antifungal effects beyond the time in which that it was possible to detect the drug.
*Hope et al.* , 2019** Hope W, Stone NRH, Johnson A, McEntee L, Farrington N, Santoro-Castelazo A, et al. Fluconazole monotherapy is a suboptimal option for initial treatment of cryptococcal meningitis because of emergence of resistance. mBio. 2019;10(6):e02575-19.	Murine model of meningoencephalitis	C. neoformans (ATCC 208821) 4 µg/mL	125 and 250 mg/kg once a day of FLU	Plasma, cerebrum and CSF	CLSI microdilution method	3-compartment PK model linked to two equations that describe the time course of the densities of susceptible and resistant subpopulations	The PK/PD model described that FLU at clinically relevant exposures does not cause fungi eradication in the central nervous system and is ineffective in preventing the rapid onset of resistance.
*Kovanda et al.* , 2019** Kovanda LL, Giamberardino C, McEntee L, Toffaletti DL, Franke KS, Bartuska A, et al. Pharmacodynamics of isavuconazole in a rabbit model of cryptococcal meningoencephalitis. Antimicrob Agents Chemother. 2019;63(9):e00546-19.	Rabbit model of cryptococcal meningoencephalitis	C. neoformans (ATCC 208821) 0.008 µg/mL for ISA and 1 µg/mL for FLU	ISA orally and FLU i.v.	Plasma, brain and CSF	CLSI M27-A3 macrodilution method	Population PK/PD mathematical model was performed using nonparametric estimation with Pmetrics software using five differential equations	Similar significant reductions in fungal load on the brain and CSF were observed in rabbits treated with ISA sulfate and FLU. Showing that the treatment of cryptococcal meningoencephalitis with the two drugs are similar.

Ref.	Patients/animal model characteristics	Yeast and MIC	Drug and Dosage regimen	Sample	Model	Covariates	PK parameters	Outcomes
*Alobaid et al., 2016*Alobaid AS, Wallis SC, Jarrett P, Starr T, Stuart J, Lassig-Smith M, et al. Effect Of Obesity On The Population Pharmacokinetics Of Fluconazole In Critically Ill Patients. Antimicrob. Agents Chemother. 2016;60:6550–6557.	Critically ill nonobese, obese and morbidly obese patients	n.a.	n.a	Plasma	Two-compartment popPK model	CL_CR for FLU clearance and BMI for FLU Vc	CL = 0.95 L/h Vc = 15.10 L KCP = 5.41 h^-1 KPC = 2.92 h^-1	In this study, which included patients with severe obesity and morbid obesity, it was shown that the clearance of FLU was correlated with measured CL_CR, and Vc was better correlated with BMI.
*Alves et al., 2017*Alves IA, Staudt KJ, De Miranda Silva C, De Araujo GL, Dalla Costa T, De Araujo BV. Influence of experimental cryptococcal meningitis in wistar rats on voriconazole brain penetration assessed by microdialysis. Antimicrob. Agents Chemother. 2017;61:1–8.	Model of cryptococcal meningoencephalitis in rats	C. neoformans (ATCC 28957) 0,03 - 0,5 μg/mL	5 mg/kg i.v. of VRC	Plasma and µd	Two compartments and MM elimination describes the VRC concentration-time profile in plasma and tissue	Infection was included in V₂ and V_M	V_1pop = 0.241 L V_{2 healthy} = 0.352 L V_{2 infected} = 0.216 L Β _{V2 infected} = -0.487 K_{12 pop} = 8.530 h^-1 K_{21 pop} = 6.130 h^-1 V_{M healthy} = 0.324 µg/mL V_{M infected} = 0.186 µg/mL Β _{VM infected} = -0.557 k_M = 0.540 µg/mL	In this study, the brain penetration rate showed an increase in exposure in infected animals when compared to healthy animals. The levels of VRC that reached the infected tissues were higher than the MIC, which indicates a potential treatment for cryptococcal meningitis.
*Alves et al., 2018* Alves IA, Staudt KJ, Carreño FO, De Araujo GL, De Miranda Silva C, Rates SMK et al. Population pharmacokinetic modeling to describe the total plasma and free brain levels of fluconazole in healthy and Cryptococcus Neoformans infected rats: How does the infection impact the drug’s levels on biophase? Pharm Res. 2018;35:1–10.	Model of cryptococcal meningoencephalitis in rats	C. neoformans (ATCC 28957) 4 μg/mL	20 mg/kg i.v. of FLU	Plasma and µd	Two compartments describe the FLU concentration-time profile in plasma and tissue	Infection was included in k₂₁, V₁ and V₂	V_{1 pop} = 0.176 L Β _{V1 WT} = 1.080 V_{2 pop} = 0.059 L Β_{V2 WT} = 0.951 K_{21 pop} = 6.260 h^-1 Β_{k21 CAT} = -0.635 K_{12 pop} = 1.612 h^-1 K_{10 pop} = 0.156 h^-1	This study showed a brain penetration rate and increase in exposure in infected animals when compared to healthy animals. This study shows also, that when used in monotherapy, FLU is limited to treat a cryptococcal meningoencephalitis.
*Stott et al., 2018*Stott KE, Beardsley J, Kolamunnage-Dona R, Castelazo AS, Kibengo FM, Mai NTH, et al. Population pharmacokinetics and cerebrospinal fluid penetration of fluconazole in adults with cryptococcal meningitis. Antimicrob Agents Chemother. 2018;27;62(9):e00885-18.	Adults with cryptococcal meningitis	C. neoformans 8 μg/mL	800 mg q24h orally of FLU and 1mg/kg q24h of Amp-B deoxycholate	Plasma and CSF	Four-compartment PK model	Patient's weight was associated with the estimated volume of distribution	K_a = 8.78 h^-1 SCL/F = 0.72 L/h V_c/F = 18.07 L K_cp = 12.20 h^-1 K_pc = 18.10 h^-1 K_cs = 35.43 h^-1 K_sc = 28.63 h^-1 V_cns/F = 32.07 L	The popPK model suggests that current FLU regimens are unsuitable for induction therapy for cryptococcal meningitis. What can be attributed to the notion that FLU is a fungistatic agent.
*Alhadab et al., 2019*Alhadab AA, Rhein J, Tugume L, Musubire A, Williams DA, Abassi M, et al. Pharmacokinetics-Pharmacodynamics Of Sertraline As An Antifungal In Hiv-Infected Ugandans With Cryptococcal Meningitis. J Pharmacokinet Pharmacodyn. 2019;46:565–576.	HIV-infected Ugandan patients with cryptococcal meningitis	Cryptococcus clinical isolates Mean 4 μg/mL	100, 200, 300, 400 mg/day of SER; 0.7 – 1.0 mg/kg per day and 800 mg/day of FLU	Plasma and CSF	One-compartment PK model with first-order absorption and elimination an exploratory sigmoidal E_max model	The use of antiretrovirals was included as a covariate in CL/F	CL/F = 52.7 L/h V/F = 1780 L ART CL = 0.948 K_a = 0.101 h^-1	SER oral clearance was 1.95 times higher in patients receiving ART, which represents 49% less exposure to the drug. SER increased the exposure of FLU in the brain which increased the fungal clearance of CSF.

Ref.	Patients/animal model characteristics	Drug and Dosage regimen	Model	PK/PD target	Outcomes
*Alhadab et al., 2019*Alhadab AA, Rhein J, Tugume L, Musubire A, Williams DA, Abassi M, et al. Pharmacokinetics-Pharmacodynamics Of Sertraline As An Antifungal In Hiv-Infected Ugandans With Cryptococcal Meningitis. J Pharmacokinet Pharmacodyn. 2019;46:565–576.	Critically ill nonobese, obese, and morbidly obese patients	200 mg/d of FLU, weight-based loading dose of 12 mg/kg and maintenance dose of 6 mg/kg	Two-compartment popPK model	fAUC/MIC of 100	In this study it was demonstrated that a FLU dose of 200 mg daily was insufficient to achieve fAUC/MIC of 100 for pathogens with MICs of >2 mg/liter in patients with BMI of >30 kg/m² and loading dose of 12 mg/kg and maintenance dose of 6 mg/kg/day achieved pharmacodynamic targets for higher MICs.
*Stott et al., 2018*Stott KE, Beardsley J, Kolamunnage-Dona R, Castelazo AS, Kibengo FM, Mai NTH, et al. Population pharmacokinetics and cerebrospinal fluid penetration of fluconazole in adults with cryptococcal meningitis. Antimicrob Agents Chemother. 2018;27;62(9):e00885-18.	Adults with cryptococcal meningitis	400 mg q24h, 800 mg q24h, 1,200 mg q24h, and 2,000 mg q24h of FLU	Four-compartment PK model	AUC/MIC of ≥389.3	This study provides the PD rationale for the long-recognized fact that FLU monotherapy is an inadequate induction regimen for cryptococcal meningitis
*Alves et al., 2018* Alves IA, Staudt KJ, Carreño FO, De Araujo GL, De Miranda Silva C, Rates SMK et al. Population pharmacokinetic modeling to describe the total plasma and free brain levels of fluconazole in healthy and Cryptococcus Neoformans infected rats: How does the infection impact the drug’s levels on biophase? Pharm Res. 2018;35:1–10.	Model of cryptococcal meningoencephalitis in rats	125 mg/kg dose for rats and 400–2000 mg for humans of FLU	Two-compartmental popPK model	fAUC/MIC >389	This study demonstrated which FLU is limited use in monotherapy to the treatment of cryptococcosis in rats and humans to value of MIC >8 μg/mL.

Ref.	Software	Drug and ADM	Study type	Population	Dose Regimen	Main Results	Acceptance Criteria	Conclusion
*Li et al., 2018*Li 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., 2018*Hens 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., 2018*Zhao 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., 2018*Watt 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., 2013*Frechen 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., 2017*Hens 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., 2017*Liu 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., 2018*Silva 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., 2018*Johnson 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., 2017*Qi 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.

[1] E-mail: bibiana.araujo@ufrgs.br

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The role of modeling and simulation to improve the treatment of fungal infections caused by Cryptococcus: A literature review

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