Posaconazole Injection

1. Treatment of invasive aspergillosis (IA)
Clinical status: It is a second-line treatment for invasive aspergillosis, especially pulmonary aspergillosis, and is suitable for patients who are intolerant to voriconazole or have failed treatment.

A clinical study published in The Lancet in 2021 showed no significant difference in 42 day all-cause mortality between posaconazle and voriconazole in the initial treatment of IA (15% vs 17%), and the incidence of adverse reactions related to eye disease and mental illness was lower in the posaconazle group (3% vs 8%).

Medication plan:
Load dose: 300mg on the first day, once every 12 hours (q12h);
Maintenance dose: 300mg from the second day, once daily (qd), intravenous infusion time should exceed 90 minutes;

Course of treatment: usually lasting 6-12 weeks, adjusted according to the site of infection and patient response. For example, pulmonary aspergillosis needs to be treated until imaging improves and symptoms disappear, while central nervous system aspergillosis needs to extend the course of treatment to more than 12 weeks.

Mechanism of action: Posaconazle inhibits fungal cytochrome P450 dependent 14 α - demethylase, blocks ergosterol synthesis, and leads to changes in fungal cell membrane permeability. Its minimum inhibitory concentration (MIC) against Aspergillus fumigatus is 0.25-1mg/L, significantly lower than fluconazole (>64mg/L), and it still maintains activity against fluconazole resistant strains.

2. Prevention of invasive fungal infections
High risk population:
Patients with hematological malignancies: those who undergo chemotherapy leading to neutropenia (neutrophil count<0.5 × 10 ⁹/L and duration>10 days) have an incidence of invasive fungal infections as high as 20% -30%;
Hematopoietic stem cell transplantation (HSCT) recipients: Patients with graft-versus-host disease (GVHD) have a 5-8 fold increased risk of infection due to immunosuppressive therapy;

Solid organ transplant recipients: The incidence of aspergillosis after lung transplantation is 10% -20%, and the risk of candidiasis is significantly increased after liver transplantation.
Prevention plan:
Dosage: 300mg, qd, intravenous infusion;
Course of treatment: From neutropenia to recovery (neutrophil count>0.5 × 10 ⁹/L and lasting for 3 days), or end of immunosuppressive therapy;

Evidence support: A randomized controlled trial involving 585 patients showed that the incidence of breakthrough fungal infections was reduced by 52% (4% vs 9%) in the posaconazle prevention group compared to the fluconazole group, and there was no significant difference in all-cause mortality.

Weight<40kg: 4.5-6mg/kg on the first day, q12h; The maintenance dose is 4.5-6mg/kg, qd, with a maximum dose of 300mg/d;
Weight ≥ 40kg: Administer according to the adult dose (300mg/d);
Route of administration: Priority should be given to peripheral vein catheterization (PICC) or deep vein administration to avoid thrombophlebitis caused by multiple infusions into the peripheral vein.

Clinical data: A study targeting adolescents aged 13-17 showed that the blood concentration compliance rate of posaconazole injection (trough concentration ≥ 0.7mg/L) reached 85%, and the incidence of adverse reactions was similar to that of adults (nausea 12%, diarrhea 8%).

2. Patients with liver and kidney dysfunction
Liver dysfunction:
Mild to moderate (Child Pugh A/B grade): No dose adjustment is required, but liver function (ALT/AST, bilirubin) needs to be monitored;

Severe (Child Pugh C grade): Limited data, it is recommended to use with caution and closely monitor.
Renal insufficiency:
Mild to moderate (eGFR ≥ 50mL/min): No dose adjustment required;
Severe (eGFR<50mL/min): The benefits/risks need to be carefully evaluated as sulfobutyl ether beta cyclodextrin (SBECD) may accumulate in injection excipients. If necessary, monitor serum creatinine levels and switch to enteric coated tablets (SBECD not absorbed) if necessary.

1. Treatment of Trichoderma
Clinical challenge: The mortality rate of mucormycosis is as high as 50% -80%. Traditional amphotericin B liposomes (L-AmB) pose a risk of nephrotoxicity, while posaconazle has become an important choice due to its good cerebrospinal fluid penetration (concentration 8 times the blood drug concentration).

Joint plan:

Initial treatment: L-AmB (5mg/kg/d) combined with posaconazle (300mg, q12h x 1 day, followed by 300mg/d);
Sequential treatment: After the condition stabilizes, L-AmB is reduced to 3mg/kg/d, and posaconazle is converted to enteric coated tablets (300mg/d);

Evidence support: A retrospective study showed that the combination therapy group had a 75% relief rate of mucormycosis, significantly higher than the monotherapy group (45%).

2. Intensive treatment for critically ill patients
Applicable scenarios: Patients with hemodynamic instability, multiple organ dysfunction syndrome (MODS), or breakthrough fungal infections.

Plan optimization:
Triazoles+echinocandins: Posaconazle (300mg/d) combined with caspofungin (70mg loading dose, followed by 50mg/d), covers dual infections of Aspergillus and Candida;
Pharmacokinetic monitoring: In critically ill patients, hypoalbuminemia (albumin<25g/L) may lead to an increase in free drug concentration, and the target trough concentration needs to be adjusted to 0.5-1.0mg/L.

1. Therapeutic drug monitoring (TDM)
Necessity: The pharmacokinetics of posaconazole injection vary greatly among individuals (AUC coefficient of variation reaches 50%), and blood drug concentration is closely related to efficacy/toxicity.
Monitoring plan:

Sampling time: Blood collection on the 5th day after the first medication (steady-state concentration);
Target value:
Prevention: Grain concentration ≥ 0.7mg/L;
Treatment: Valley concentration ≥ 1.0-1.25mg/L;
Method: High performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) with a detection limit of 0.01mg/L.

2. Drug interaction management
CYP3A4 substrate:
Strong inhibitors (such as voriconazole and clarithromycin): avoid combination therapy, and if necessary, reduce the dose of posaconazle to 200mg/d;
Substrate (such as tacrolimus, sirolimus): When used in combination, the dose of tacrolimus should be reduced to 0.5mg/week and the whole blood concentration should be monitored (target value 5-15ng/mL).

HMG CoA reductase inhibitors:
Taboo combination use: Posaconazle can increase the blood concentration of atorvastatin by 9 times, leading to an increased risk of rhabdomyolysis. It is necessary to switch to pravastatin (non CYP3A4 metabolism).