1. Pharmacokinetic/Pharmacodynamic Dosing
Fluconazole
Pharmacokinetic/Pharmacodynamic Dosing

2. Situation
Current guidelines give dosing ranges for selected indications
Single order sets for empiric treatment may reduce errors & improve efficacy
Pharmacokinetic (PK)/Pharmacodynamic (PD) data may be used to clarify dosing recommendations
Objectives:
Review fluconazole PK/PD Review of efficacy studies Proposed dosing ranges

3. Background
Nosocomial Candidemia is the 3rd or 4th most common cause of health-care related bloodstream infections. (PG Pappas, 2015)
> 90% are caused by: C. albicans, C. glabrata, C. tropicalis, C. parapsilosis or C. krusei
Non-albicans Candida comprises almost 50% of isolates
Risk factors for colonization of Candida include: low gestational age, vaginal delivery, increased length of antibiotic use, steroids, intubation, central line use, length of parenteral nutrition & immunosuppression.

4. Serum concentrations of fluconazole may be decreased by increases in Vd due to fluid shifts, hypoalbuminemia, changes in tissue permeability (Appendix 1, Table 1), mechanical ventilation, cardiac output or ascites. Clearance may be increased by malignancy, critical illness or young age while organ dysfunction may decrease clearance. (S Mahipal, 2012) Fluconazole’s half-life (t1/2) may range from 20 to 70 hours based on age and renal function both of which should be considered when choosing a dosing interval. Postantifungal effects (PAFE) have been reported to be minimal (in situ) or up to 3.6 hours (with serum) and may contribute to treatment efficacy (S Mahipal, 2012) (Andes, 2004) (F Minguez, 1994)
Fluconazole
well absorbed & widely distributed in aqueous fluids
Volume of distribution, Vd ~ 0.6 L/kg
MOA: inhibits synthesis pathway for ergosterol; interferes with cell membrane formation
Fungistatic against Candida species.
Drug Interactions: strong inhibitor of CYP2C9 & CYP2C19; moderate CYP 3A4 inhibitor
Serum concentrations may be decreased by increases in Vd:
Fluid shifts, hypoalbuminemia, tissue permeability changes, mechanical ventilation, cardiac output, ascites, age (< 12 years, Table 2&3)
Half-life & Clearance vary based on
Malignancy, critical illness (increased clearance)
Organ dysfunction (decreased clearance) ~ 80% renal excretion
Age
Post antifungal effect up to 3.6 hours measured
Age
2 weeks
1 month
9-13 months
5-15 years
Adult
Half-life
~ 79 hours
~32 hours
~ 25 hours
~ 16 hours Vd
~1.6 L/kg
~1.1 L/kg
~1.2 L/kg
~0.9 L/kg
~0.6 L/kg
(S Mahipal, 2012) (Andes, 2004) (F Minguez, 1994) (Piper, 2011) ,Table 2, Table 3, Appendix 1 (Table 4)

5. Fluconazole Bioavailability > 90%
similar activity against many Candida species
Table 2: Candida Clinical Breakpoints (mcg/mL) for Fluconazole (PG Pappas, 2015)
Candida Organism S
SDD R
C. albicans
< 2 4
> 8
C. glabrata
---- 32
> 64
C. parapsilosis
C. tropicalis
C. krusei
-----
S=Susceptible, SDD= Susceptible Dose Dependent, R=Resistant: EUCAST Susceptible < 2 mcg/mL, Resistance > 4 mcg/mL

6. Fluconazole Serum Concentration Calculated AUC mg*h/L**
Table 3: Dosing in Children equivalence to adult dosing & Fluconazole Serum Concentrations (Pfizer, 2014) , Vitek Yeast Panel, 2015
Pediatric
Adults
Fluconazole Serum Concentration
Calculated AUC mg*h/L**
infants
3 mg/kg
100 mg
1-2 mcg/ml
134
6 mg/kg
200 mg
2-4 mcg/ml
268
12* mg/kg
400 mg
4-8 mcg/ml
536
Saxen < 2 weeks old Lambda = Clearance/Vd /h, , /h = /h
Piper 6 to 59 days days , , , = days , days = 0.064
Average of < 19 days data = 0.014
Clearance Wade mg/kg/720 mgh/l = 17 mL/h kg
Fluconazole susceptible breakpoints for Candida =< 2 mcg/mL; SDD < 8 mcg/mL
*Older children clearances (Cl) ~ adults ** Assuming ~ 100% bioavailability & elimination constant (Ke) ~ 0.014/h (infants < 3 weeks) AUC = dose/Cl; Cl ~ Ke * Vd (1.6 L/kg) (Piper, Saxen, Wenzl, Lee, Wade, Coates, Tables 2 & 3)

7. Fluconazole Dosing Better clinical outcomes predicted for
Area under the curve (AUC) > 400 mg*h/L
AUC/MIC > (MIC < 8)
in vivo (mouse) studies demonstrated ~ 50% efficacy for AUC/MIC ~ 25
Adult studies had higher cure rates for AUC/MIC ~ 25-50
Adults, treated with 50 to 800 mg fluconazole (Andes, 2004, Table 2)
Candidemia in adults
74% success dose/MIC > 50 vs 8 % success dose/MIC < 50 (CJ Clancy, 2005), (A Louie, 1998)
For prophylaxis:
Decreased infection rates demonstrated; no decrease in mortality (very low birth weight infants)
Average NNT of 14 for a 3 mg/kg dose
Average NNT of 8 for a 6 mg/kg dose
Predicted serum concentration range 4-23 mcg/mL.
Trend toward higher dosing for prevention.
(KC Wade, 2015) (S Mahipal, 2012) (L Piper, 2011)h (KC Wade, 2008) (KC Wade, 2009) (Andes, 2004), Table 2 & 3

8. Fluconazole Dosing Intervals
Treatment and prophylaxis dosing should be adjusted based on age & renal clearance. (L Piper, 2011).
Half-life decreases from ~ 80 h in neonates to ~ 25 h in infants at 1 month.
Dosing every 72 h for the 1st 2 weeks recommended
premature neonates (Pfizer 2014)
Other tested dosing intervals include every 72 hours (weeks 1 & 2), every 48 hours weeks 3 & 4, daily thereafter
Monitoring levels if using for more than 1 week may ensure dosing & dosing intervals remain effective.
(KC Wade, 2015) (S Mahipal, 2012) (L Piper, 2011)h (KC Wade, 2008) (KC Wade, 2009) (Andes, 2004).

9. Fluconazole Dosing Current Guidelines
Disease state
2016 IDSA Recommended dosing for children
Candida Endophthalmitis
12 mg/kg loading mg/kg daily
CNS Candidiasis
6-12 mg/kg daily
Urinary Tract Candida Infections
Pyelonephritis: 3-6 mg/kg daily
Candida Intravascular (including endocarditis & infected implantable)
6 -12 mg/kg daily Step-down therapy OR Long term suppression  
Esophageal
3-6 mg/kg daily or IV 6 mg/kg daily
De-escalation: 3-6 mg/kg daily
Prophylaxis
Neonatal Prophylaxis
3-6 mg/kg twice weekly
Consensus guidelines for the treatment of yeast infections in the hematology, oncology, and intensive care setting, (SC Chen, 2014)
Infections Hematology, Oncology, ICU
12 mg/kg/day with 25 mg/kg loading dose day 1
CNS candidiasis
2nd line: 6-12 mg daily
Ocular candidiasis
6 -12mg/kg daily

10. Distribution of Fluconazole
Tissue or Fluid
Ratio of Fluconazole Tissue(Fluid)/ Plasma Concentration
Cerebrospinal Fluid
Saliva 1
Sputum
Blister
Urine 10
Normal Skin
Nails
Blister skin 2
Vaginal Fluid
Vaginal Tissue

11. Dosing Recommendations (normal renal function) Use upper range of IDSA guideline dosing to achieve dose/MIC > 50
Indication
Age
Dosing
Interval
Dose*
Observed
AUC
Predicted Serum
Concentration
Treatment
Critically Ill
Candidemia
Endopthalmus
0 to 2 weeks
72 hours
12 mg/kg
Consider
25 mg/kg
Loading
Dose
(LD)
~ 600 mg*h/L
Range:
mg*h/L
15-23 mcg/mL
2 to 4 weeks
48 hours**
>4 weeks
24 hours
Malignancy
~ 60% of non malignant patients
Neonatal
Prophylaxis
(High Risk
Populations)
6 mg/kg LD
123 mg*h/L
4-13 mcg/mL
48 hours
Monitor serum creatinine (SCr) & LFT; adjust dosing for SCr increases above 1 mg/dL. (KC Wade, 2015). Monitor steady state trough serum concentrations of fluconazole for long term treatment * Reduce dose 50% for renal impairment.
**Package insert recommends daily. Maximal dose 600 mg/day for pediatric populations (Pfizer, 2014).

12. Dosing Notes
Maximum dose in pediatric population: 600 mg/day (Pfizer, 2014)
Obesity: Use Total Body Weight; consider higher end of dosing range
Based on single case report in adults
Dosing & MIC’s (Where does dose/MIC > 50 come from?)
Pharmacokinetic studies showing dose linearly proportional to AUC (humans up to 2000 mg, IV) AUC24h = (dose) (mg*h/L) slope = DAUC/Ddose
AUC~ bioavailability * Dose/Clearance
Oral fluconazole bioavailability > 90% ~ 1
Neonates longer half-life offset by larger volume of distribution
Estimated Clearance by age (L/kg)
< 2 weeks
~ 1 month
9month
5-15 years
Adults
0.014
0.024
0.033
0.039
0.017