test 2 part 2 Flashcards
Continuous Infusion Regimen
- Rate of drug entry into body is constant
* Plasma concentration of drug rises until steady state is reached
Steady-state Plasma
Concentration (Css)
•Drug elimination equals the rate of administration
Relationship between infusion rate and concentration steady-state (Css)
- Css is directly proportional to infusion rate
* Example: infusion rate doubled, then Css is doubled
Relationship between clearance and concentration steady-state (Css)
- Inversely proportional to clearance of drug
- Anything that decreases clearance will increase Css (liver/renal disease)
- Anything that increases clearance will decrease Css (high metabolism, diarrhea)
What is the Length of Time to Reach Css?
- Rate constant to reach steady state is equal to the rate constant for total body elimination of drug (t1/2)
- Sole determinate of the rate that a drug achieves steady state is the half-life
Steady-state concentration based on half-life
•Drug concentration approaches 50% of Css after the first half-life
- 75% at two half-lives
- 87.5% at three half-lives
- 93.75% at four half-lives
- 96.875% at five half-lives
- usually will reach steady state between 4 and 5 half-lives
Fixed-dose/fixed-time Regimens (IV)
- More convenient than IV infusion
* Results in fluctuating levels of drug
Intravenous Fixed-time Regimens
- Drug given at intervals shorter than 5 half-lives
- Some drug from the first dose remains in body when the second dose is administered, some drug from the second dose remains when the third dose is given, and so on
Oral Fixed-dose Regimens
•Css is influenced by the rate of absorption and rate of elimination
Optimization of Dose
•Goal is to maintain drug plasma concentration within the therapeutic window
Therapeutic Window
•Safe range between the minimum therapeutic concentration and the minimum toxic concentration
Two Ways to Achieve Optimization of Dose
- Loading dose
* Maintenance dose
Loading Dose
•Administered to achieve rapid desired plasma levels of drug
•Single dose or series of doses
•Used with drug that have longer half-lives
•Long time to reach Css
•Followed by maintenance dose
-dependent on volume and distribution
Loading Dose Equation (IV)
Loading Dose (LD) = Vd x Css
A patient weighs 60 kg and a target plasma concentration of 7.5 mg/L of Theophylline is required. The Vd of Theophylline is 0.5L/kg. What is the IV loading dose for this patient?
LD = 0.5 L/kg x 7.5 mg/L = 3.75 mg/kg x 60 kg = 225 mg
Maintenance Dose (MD)
•Maintain plasma concentration of drug within the therapeutic range
Maintenance Dose Equation (IV)
Maintenance Dose (MD) = CL x Css
A patient weighs 60 kg, the target Theophylline plasma concentration is 10 mg/L. Clearance of Theophylline is 2.8 L/hr. A loading dose of Theophylline has been given to relieve acute bronchial asthma in this patient. What would be the maintenance dose for this patient?
2.8 L/hr x 10 mg/L = 28 mg/hr / 60 kg = 0.47 mg/kg/hr
Dosage Adjustment
- Diminished renal or hepatic blood flow
- Hemorrhage, heart failure
- Renal/hepatic disease
- Cirrhosis, kidney failure
- Children
- Elderly
- Increased hepatic blood flow, increased metabolism, and decreased protein binding
Drug Approval Process
- in vitro studies
- animal testing
- clinical testing
- marketing
Investigation New Drug Exemption Application (IND)
- Submitted by the manufacturer to the FDA
- Includes all the preclinical data collected up to time of submission
- Pharmacological effects
- Hepatic and renal monitoring
- Blood and urine test
- Reproductive effects
- carcinogenicity
- Includes detailed proposal for clinical trials
Clinical Trials
- Divided into three phases
- Provides information for a New Drug Application (NDA)
- NDA includes all results of preclinical and clinical testing and provides the request for FDA approval
Phase 1 (clinical trial)
- Evaluates dose-response relationship
- Performed on small number of healthy volunteers
- (20-100)
Phase 2 (clinical trial)
- Performed on a moderate number of patients with the target disease
- (100-200)
- Placebo or positive control included
- Single-blinded or double-blinded design
- Evaluates efficacy
Phase 3 (clinical trial)
- Performed on many patients, in many centers, with many clinicians
- 1000-5000
- Includes placebo and positive controls
- Double-blinded design
- Further evaluation of therapeutic effect and discovery new toxicities
- Comparison with older drug therapies
- If successful completion, NDA is submitted to the FDA
- If NDA approved, drug can be marketed and Phase 4 begins
Phase 4 (clinical trial)
- Post-marketing surveillance
- Evaluate any toxicities that occur
- Manufacturers are required to report any adverse drug reactions to the FDA on a regular basis
- Not as rigidly regulated as the other phases
