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Zorluk: OrtaPharmacokinetic and Pharmacodynamic Principles

A 47-year-old woman is evaluated in the infectious disease clinic for treatment of a refractory systemic fungal infection following a recent hematopoietic stem cell transplant. She is currently taking tacrolimus and prophylactic acyclovir. The physician plans to start an oral formulation of a novel triazole antifungal agent. The patient's current body weight is 75 kg75 \text{ kg}. According to the pharmacokinetic profile of this new medication, it has an oral bioavailability (FF) of 50%50\%, a volume of distribution (VdV_d) of 2.0 L/kg2.0 \text{ L/kg}, and a systemic clearance (ClCl) of 0.04 L/hr/kg0.04 \text{ L/hr/kg}. The therapeutic goal is to maintain an average steady-state plasma concentration (Css,avgC_{ss,avg}) of 15 mg/L15 \text{ mg/L}. The dosing regimen will consist of administration every 8 hours.

What is the required oral dose in milligrams (mg\text{mg}) to be given every 8 hours to achieve the target steady-state concentration?

Cevap: 720 mg

Cevap

720
The maintenance dose is designed to replace the amount of drug eliminated since the previous dose. The rate of drug elimination at steady state is the product of systemic clearance and the target steady-state concentration. Once the elimination rate is determined, it is multiplied by the dosing interval to find the total drug cleared. Finally, this amount is divided by the oral bioavailability fraction to account for incomplete absorption, yielding 720 mg720 \text{ mg}.

Adım Adım Çözüm

1
Determine the patient's absolute systemic clearance.
3.0 L/hr3.0 \text{ L/hr}
Clearance is given in a weight-adjusted format (L/hr/kg\text{L/hr/kg}) and must be multiplied by the patient's weight (75 kg75 \text{ kg}) to find the total systemic clearance.
2
Calculate the amount of drug eliminated during one dosing interval.
360 mg360 \text{ mg}
The elimination rate at steady state equals clearance multiplied by the target concentration (3.0 L/hr×15 mg/L=45 mg/hr3.0 \text{ L/hr} \times 15 \text{ mg/L} = 45 \text{ mg/hr}). Over an 8-hour interval, 45×8=360 mg45 \times 8 = 360 \text{ mg} is eliminated.
3
Adjust the required dose for oral bioavailability.
720 mg720 \text{ mg}
Because only 50%50\% of the oral dose reaches systemic circulation (F=0.50F = 0.50), the administered dose must be twice the amount eliminated (360 mg/0.50=720 mg360 \text{ mg} / 0.50 = 720 \text{ mg}).

Anahtar Kavram

Maintenance dose calculation incorporating bioavailability, systemic clearance, and dosing interval.
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