Peak plasma concentration at steady state

Dipyridamole Peak plasma levels of dipyridamole are achieved approximately 2 hours after administration of a daily dose of 400 mg dipyridamole and aspirin combination (given as 200 mg twice daily). The peak plasma concentration at steady-state is approximately 1.98 mcg/mL and the steady-state trough concentration is approximately 0.53 mcg/mL. 

Maximum or peak plasma concentration at steady state against the number of administered doses. 

For example, calculated or reported value of R = 2 simply suggests that the peak plasma concentration at steady state will be twice the peak plasma concentration for the first dose. Analogously, the minimum plasma concentration at steady state will be two times as high as the minimum plasma concentration for the first dose. An R value of 2 also means that the "average" plasma concentration at steady state will be twice the "average" plasma concentration for the first dose. This is applicable for an intravenous bolus of dmg. Therefore, knowledge of the calculated or reported R value permits prediction of the... 

Therefore, in this example, if the subsequent doses are administered at a 24 h interval (i.e. dosing interval equals one half life of the drug), the peak steady-state concentration, the trough steady-state concentration and the "average" steady-state concentration will be twice the corresponding plasma concentration for the first dose. Is it accurate to say that if the peak plasma concentration at steady state is twice the peak plasma concentration for the first dose then the dosing interval represents the half life of the drug ... 

Fluctuation (O) is simply a measure of the magnitude of variation in, or the differences between, the peak and trough plasma concentrations at steady state or, by some definitions, the peak and "average" plasma concentrations at steady state. 

Fluctuation, therefore, is simply a measure of the ratio of the steady-state peak or maximum plasma concentration to the steady-state minimum or trough plasma concentration of a drug or the ratio of the peak or maximum steady-state concentration to the "average" plasma concentration at steady state for the chosen dosage regimen. 

Drug fluctuation is the ratio of peak and trough plasma concentrations at steady state. 

Since the right side of Eq. 12.9 is always positive, it is apparent that the maximum plasma concentration at steady state occurs at an earlier time than that following the administration of a single dose. Furthermore, the time at which the maximum plasma concentration is observed following the first dose (i.e. t ax) is often the time at which the plasma is sampled after the administration of subsequent doses to assess peak plasma concentration. Mathematical principles clearly suggest that this would not be a sound practice since the time at which a maximum plasma concentration occurs is not constant until steady state is attained. 

Figure 14.1 Multiple internnittent infusions shown in a rectilinear plot. plasma drug concentration (Cpk)ss, peak drug concentration at steady state (Ctr)ss. trough drug concentration at steady state t, dosing interval t f, time infusion is running.

The pharmacokinetics of lidocaine in patches have been investigated in two studies. In 20 healthy volunteers, 5% lidocaine patches were applied for 18 hours/day on 3 consecutive days (69). The mean peak concentrations on days 1, 2, and 3 were 145,153, and 154 ng/ml respectively the median values of were 18.0, 16.5, and 16.5 hours and the mean trough concentrations were 83, 86, and 77 ng/ml. The patches were well tolerated local skin reactions were generally minimal and self-limiting. In 20 healthy volunteers, 4 lidocaine patches were applied every 12 or 24 hours on 3 consecutive days (67). The mean maximum-plasma lidocaine concentrations at steady state were 225 and 186 ng/ml respectively. There was no loss of sensation at the site of application. No patient had edema and most cases of erythema were very slight. No systemic adverse events were judged to be related to the patches. 

Time to obtain plasma sample Most drug samples are obtained as trough concentrations at steady state. If a peak sample is to be obtained, the absorption/distribution phase should be avoided. Recording the time of sampling is important. 

Absorption-The oral bioavailability at steady-state is estimated to be 15% and 19% for 7.5 and 15 mg tablets, respectively. Peak plasma concentrations are reached approximately 7 hours after multiple dosing, and steady-state plasma concentrations are achieved by the sixth day of dosing. 

Amphetamine mixture - Peak plasma concentrations occur in about 3 hours (Adderall) and 7 hours (Adderall XR). Elimination half-life is 10 to 13 hours in adults and 9 to 11 hours in children. Extended-release amphetamine mixture capsules demonstrate linear pharmacokinetics. There is no unexpected accumulation at steady state. Food does not affect the extent of absorption of extended-release amphetamine mixture capsules, but prolongs T ax by 2.5 hours. 

Absorption/Distribution - Tiagabine is nearly completely absorbed (more than 95%), with an absolute oral bioavailability of about 90%. Food slows the absorption rate but does not altering the extent of absorption. Absorption is rapid, with peak plasma concentrations occurring at approximately 45 minutes after an oral dose. Steady state is achieved within 2 days. 

Relative to an IV dose of 20 mg, the absolute oral bioavailability of metoclopramide is approximately 80%. Peak plasma concentrations occur at approximately 1 to 2 hours after a single oral dose. Similar time to peak is observed after individual doses at steady-state. The area under the drug... 

Indinavir was rapidly absorbed in the fasted state, with a time to peak plasma concentration of 0.8 0.3 hours (mean S.D.) (n=l 1). A greater than dose-proportional increase in indinavir plasma concentrations was observed over the 200-1000 mg dose range. At a dosing regimen of 800 mg every 8 hours, the steady-state area under the plasma concentration time curve (AUC) was 30,691 11,407 nM-hour (n=16), peak plasma concentration was 12,617 4037 nM (n=16), and plasma concentration eight hours post dose (trough) was 251 178 nM... 

Clinical pharmacology. Peak plasma concentrations are reached within 2-8 hours [DeBree et al. 1983], and steady-state concentrations are achieved at about 10 days, reflecting a half-life of 19-22 hours [DeVries et al. 1992]. Fluvoxamine is 77% bound to plasma proteins and is extensively metabolized by the liver [Claassen 1983]. Optimal dosing regimens for fluvoxamine range from 100 mg/day to 200 mg/day, with the maximum recommended dose being 300 mg/day. Lower doses should be used in those with significant hepatic impairment. 

Aripiprazole has been approved for treatment of schizophrenia and acute manic or mixed episodes in bipolar disorder. This medication is also indicated for maintenance treatment in bipolar I disorder. The recommended starting and target dose for aripiprazole in patients with schizophrenia is 10 or 15 mg/day. This is a once-daily dose, and patients can take the medication with or without food. Although this medication has been shown to be effective in doses ranging from 10 to 30 mg/day, doses higher than 10-15 mg have not been shown to be more effective than 10- to 15-mg doses in patients with schizophrenia. The recommended starting dose for treatment of an acute manic or mixed episode is 30 mg the recommended dose for maintenance treatment in stable patients is 15 mg/day. The elimination half-life is 75 hours, and steady-state concentrations are reached within 2 weeks. Therefore, dose adjustments are recommended every 2 weeks, to allow time for clinical assessments of the medication s effects to be observed at steady-state concentration. Peak plasma concentrations occur within 3-5 hours. At equivalent doses, the plasma concentrations of aripiprazole from the solution were higher compared with plasma concentrations associated with the tablet form. 

Donepezil is well absorbed with a relative oral bioavailability of 100% and reaches peak plasma concentrations in 3-4 h. Oral administration of Aricept produces highly predictable plasma concentrations with plasma concentrations and area under the curve rise in proportion to the dose. The terminal disposition half-life is approximately 70 h, thus administration of multiple single-daily doses results in gradual approach to steady state. Approximate steady state is achieved within 3 weeks after the initiation of therapy. Once at steady state, plasma donepezil hydrochloride concentrations and the related pharmacodynamic activity show little variability over the course of the day. Neither food nor time of administration (morning versus evening dose) affect the absorption of donepezil hydrochloride [46-51]. 

Intravenous ribavirin decreases mortality in Lassa fever and other viral hemorrhagic fevers if started early. Clinical benefit has been reported in cases of severe measles pneumonitis, and continuous infusion of ribavirin decreased virus shedding in several patients with severe lower respiratory tract influenza or parainfluenza infections. Peak plasma concentrations are approximately tenfold higher than with oral administration and occur earlier (ie, at 0.5 hours after dosing). At steady state, cerebrospinal fluid levels are about 70% of those in plasma. 

Oral verapamil has been shown to increase peak plasma levels, prolong the terminal half-life, and increase the volume of distribution at steady state of doxorubicin (282). Gigante et al. (283) performed similar studies in which the pharmacokinetics of doxorubicin in combination with verapamil given at high doses intravenously were followed for 17 patients with advanced neoplasms. The steady-state concentration and systemic and renal clearances were found to be statistically similar for various doses of verapamil and doxorubicin, and for doxorubicin administered alone. 

During continuous intravenous infusion at an average rate of 41 ig/kg/ minute to 31 subjects, a mean steady-state plasma concentration of 2.2 pg/ ml was reported norketamine and dehydronorketamine attained mean peak plasma concentrations of 1.1 pg/ml and 0.7 pg/ml, respectively, in about 3 hours the subjects awoke at an average plasma concentration of 0.64 pg/ml (J. Idvall et al., Br. J. Anaesth., 1979, 51,1167-1173). Following an intramuscular injection of 0.5 mg/kg to 6 subjects, peak plasma concentrations of 0.10 to 0.43 pg/ml (mean 0.24) were attained in about 0.3 hour norketamine attained a mean peak plasma concentration of 0.09 pg/ml at about 1 hour (J. A. Clements et al., J. pharm. Sci., 1982, 71, 539-542). 

Following a single oral dose of 150 mg to 4 subjects, mean peak plasma concentrations of 2.05 ig/ml of trazodone and 0.01 ig/ml of l-(3-chlorophenyOpiperazine were reported at about 2 hours and 2 to 4 hours, respectively (S. Cacciaeta/., J. Phartn. Pharmac., 1982,34, 605-606). Following oral administration of 25 mg three times a day to 10 subjects, steady-state serum concentrations averaged 0.7 ig/ml on the twelfth day (B. Catanese et al.. Boll, chim.-farm., 1978, 777,424-427). 

After a single oral dose of 100 mg to 21 subjects, peak plasma concentrations averaged 4.7 pg/ml at about 1 hour following oral administration of 100 mg four times a day to 10 subjects, steady-state plasma concentrations of about 3 to 4 pg/ml were reported (R. K. Nayak etal., Clin. Pharmac. Ther., 1980, 27, 395-401). 

---