Half-life pharmacokinetic modeling

Mathematical models allow for considerable data compression. Data that fill many notebooks and/or tables may be summarized by means of the few parameters of a well chosen model. Plasma concentration versus time data collected during a pharmacokinetic study in many patients may be summarized using a volume of distribution term and an elimination half-life. Other models may include more parameters, but there is always a considerable compression in the information required to describe the overall results of the study. An extensive drug stability study involving many samples stored at various elevated temperatures may be summarized as a single time for 10% decomposition at room temperature. Determination of appropriate models can be a very useful method of summarizing an experimental study. 

The half-life time t of a drug is an important pharmacokinetic parameter. In this simple model it can be obtained immediately from the solution in eq. (39.6) ... 

There was a significant negative correlation between (log) admission urinary PCP level and self-reported time since last PCP use (r= -0.53, p<0.001). Visual inspection of a graph of these two variables suggested a possible biphasic elimination curve, with the initial phase having a half-life of 5 to 7 days, and the later phase a half-life of about 30 days. However, formal curve fitting of these data to standard pharmacokinetic models (using BMDP... 

Azacitidine, a cytidine analog, causes hypomethylation of DNA, which normalizes the function of genes that control cell differentiation to promote normal cell maturation. The suspension is administered as a subcutaneous injection daily for 7 days for the treatment of myelodysplastic syndrome, a preleukemia disease. The pharmacokinetics of azacitidine are best described by a two-compartment model, with a terminal half life of 3.4 to 6.2 hours, whereas peak concentrations are achieved 30 minutes after a subcutaneous injection.7 Azacitidine has been shown to be clinically active in the treatment of myelodysplastic syndromes. The side effects include myelosuppression, renal tubular acidosis, renal dysfunction, and injection-site reactions. 

Vinblastine is another vesicant vinca alkaloid that causes myelo-suppression and less neurotoxicity than vincristine. The pharmacokinetics of vinblastine are best described by a three-compartment model, with an a half-life of 25 minutes, a 3 half-life of 53 minutes, and a terminal half-life of 19 to 25 hours.12 Vinblastine has shown activity in the treatment of bladder, breast, and kidney cancer, as well as some lymphomas. The doses of vinblastine tend to be higher on a milligram per meter squared basis than vincristine. Nausea and vomiting are minimal with vinblastine. Other side effects include mild alopecia, rash, photosensitivity, and stomatitis. 

The vesicant vinorelbine is structurally similar to vincristine and may cause many of the same side effects as vincristine. While this vesicant is administered intravenously over 6 to 10 minutes, patients should be counseled about neuropathy, ileus, and myelosuppression. The pharmacokinetics of vinorelbine are best described by a three-compartment model, with an a half-life of 2 to 6 minutes, a 3 half-life of 1.9 hours, and a y half-life of 40 hours. Vinorelbine has shown efficacy in the treatment of breast cancer and non-small cell lung cancer. Additional side effects include myelosuppression, paresthesias, and mild nausea and vomiting. 

Docetaxel, another taxane, binds to tubulin to promote microtubule assembly. The pharmacokinetics of docetaxel are best described by a three-compartment model, with an a half-life of 0.08 hours, a 3 half-life of 1.6 to 1.8 hours, and a terminal half-life of 65 to 73 hours.14 Docetaxel has activity in the treatment of breast, non-small cell lung, prostate, bladder, esophageal, stomach, ovary, and head and neck cancers. Dexamethasone, 8 mg twice daily for 3 days starting the day before treatment, is used to prevent the fluid retention syndrome associated with docetaxel and possible hypersensitivity reactions. The fluid... 

Etoposide causes multiple DNA double-strand breaks by inhibiting topoisomerase II. The pharmacokinetics of etoposide are described by a two-compartment model, with an a half-life of 0.5 to 1 hour and a (5 half-life of 3.4 to 8.3 hours. Approximately 30% of the dose is excreted unchanged by the kidney.16 Etoposide has shown activity in the treatment of several types of lymphoma, testicular and lung cancer, retinoblastoma, and carcinoma of unknown primary. The intravenous preparation has limited stability, so final concentrations should be 0.4 mg/mL. Intravenous administration needs to be slow to prevent hypotension. Oral bioavailability is approximately 50%, so oral dosages are approximate two times those of intravenous doses however, relatively low oral daily dosages are used for 1 to 2 weeks. Side effects include mucositis, myelosuppression, alopecia, phlebitis, hypersensitivity reactions, and secondary leukemias. 

Teniposide, a topoisomerase II inhibitor, is administered as an infusion over 30 to 60 minutes to prevent hypotension. The pharmacokinetics are described by a three-compartment model, with an a half-life of 0.75 hours, a (5 half-life of 4 hours, and a terminal half-life of 20 hours. Considerable variability in clearance of teniposide in children has been reported.17 Teniposide has shown activity in the treatment of acute lymphocytic leukemia, neuroblastoma, and non-Hodgkin s lymphoma. Side effects include myelosuppression, nausea, vomiting, mucositis, and venous irritation. Hypersensitivity reactions may be life-threatening. 

Topotecan inhibits topoisomerase I to cause single-strand breaks in DNA. The pharmacokinetics of topotecan can be described by a two-compartment model, with a terminal half-life of 80 to 180 minutes, with renal clearance accounting for approximately 70% of the clearance.19 Topotecan has shown clinical activity in the treatment of ovarian and lung cancer, myelodysplastic syndromes, and acute myelogenous leukemia. The intravenous infusion may be daily for 5 days or once weekly. Side effects include myelosuppression, mucositis, and diarrhea. 

Daunorubicin is an anthracycline that is sometimes referred to as an antitumor antibiotic. Daunorubicin inserts between base pairs of DNA to cause structural changes in DNA however, the primary mechanism of cytotoxicity is the inhibition of topoisomerase II. The pharmacokinetics are best described by a two-compartment model, with a terminal half-life of about 20 hours. The predominant route of elimination of daunorubicin and hydroxylated metabolites is hepatobiliary... 

Liposomal doxorubicin is an irritant, not a vesicant, and is dosed differently from doxorubicin, so clinicians need to be very careful when prescribing these two drugs. The pharmacokinetics of liposomal doxorubicin are best described by a two-compartment model, with a terminal half-life of 30 to 90 hours.20 Liposomal doxorubicin has shown significant activity in the treatment of breast and ovarian cancer, along with multiple myeloma and Kaposi s sarcoma. Side effects include mucositis, myelosuppression, alopecia, and palmar-plantar erythrodysesthesia. The liposomal doxorubicin may be less cardiotoxic than doxorubicin. 

Epirubicin inhibits both DNA and RNA polymerases and thus inhibits nucleic acid synthesis and topoisomerase II enzymes. Epirubicin pharmacokinetics are best described by a three-compartment model, with an a half-life of 4 to 5 minutes, a... 

Idarubicin inhibits both DNA and RNA polymerase, as well as topoisomerase II. The pharmacokinetics of idarubicin can best be described by a three-compartment model, with an a half-life of 13 minutes, a (3 half-life of 2.4 hours, and a terminal half-life of 16 hours.22 Idarubicin is metabolized to an active metabolite, idarubicinol, which has a half-life of 41 to 69 hours. Idarubicin and idarubicinol are eliminated by the liver and through the bile. Idarubicin has shown clinical activity in the treatment of acute leukemias, chronic myelogenous leukemia, and myelodysplastic syndromes. Idarubicin causes cardiomyopathy at cumulative doses of greater than 150 mg/m2 and produces cumulative cardiotoxic effects with other anthracyclines. Idarubicin is a vesicant and causes red-orange urine, mucositis, mild to moderate nausea and vomiting, and bone marrow suppression. 

This royal-blue-colored drug is an anthracenedione that inhibits DNA topoisomerase II. The pharmacokinetics of mitoxantrone may best be described by a three-compartment model, with an a half-life of 3 to 10 minutes, a 3 half life of 0.3 to 3 hours, and a median terminal half-life of 12 days. Biliary elimination appears to be the primary route of elimination, with less than 10% of the drug eliminated by the kidney.23 Mitoxantrone has shown clinical activity in the treatment of acute leukemias, breast and prostate cancer, and non-Hodgkin s lymphomas. Myelosuppression, mucositis, nausea and vomiting, and cardiac toxicity are side effects of this drug. The total cumulative dose limit is 160 mg/m2 for patients who have not received prior anthracycline or mediastinal radiation. Patients who have received prior doxorubicin or daunorubicin therapy should not receive a cumulative dose greater than 120 mg/m2 of mitoxantrone. Patients should be counseled that their urine will turn a blue-green color. 

While carboplatin has the same mechanism of action as cisplatin, it has a much less toxic side-effect profile than cisplatin. The pharmacokinetics of carboplatin are best described by a two-compartment model, with an a half-life of 90 minutes and a terminal half-life of 180 minutes. Carboplatin is eliminated almost entirely by the kidney by glomerular filtration and tubular secretion. Many chemotherapy regimens dose carboplatin based on an area under the curve (AUC), which is referred to... 

Mitomycin C is an alkylating agent that forms cross-links with DNA to inhibit DNA and RNA synthesis. The pharmacokinetics of mitomycin C are best described by a two-compartment model, with an a half-life of 8 minutes and a terminal half-life of 48 minutes.31 Liver metabolism is the primary route of elimination. Mitomycin C has shown clinical activity in the treatment of anal, bladder, cervix, gallbladder, esophageal, and stomach cancer. Side effects consist of myelosuppression and mucositis, and it is a vesicant. 

Denileukin diftitox is a combination of the active sections of interleukin 2 and diphtheria toxin. It binds to high-affinity interleukin 2 receptors on the cancer cell (and other cells), and the toxin portion of the molecule inhibits protein synthesis to result in cell death. The pharmacokinetics of denileukin diftitox are best described by a two-compartment model, with an a half-life of 2 to 5 minutes and a terminal half-life of 70 to 80 minutes. Denileukin diftitox is used for the treatment of persistent or recurrent cutaneous T-cell lymphoma whose cells express the CD25 receptor. Side effects include vascular leak syndrome, fevers/chills, hypersensitivity reactions, hypotension, anorexia, diarrhea, and nausea and vomiting. 

Rituximab is a monoclonal antibody to the CD20 receptor expressed on the surface of B lymphocytes the presence of the antibody is determined during flow cytometry of the tumor cells. Cell death results from antibody-dependent cellular cytotoxicity. The pharmacokinetics of rituximab are best described by a two-compartment model, with a terminal half-life of 76 hours after the first infusion and a terminal half-life of 205 hours after the fourth dose.36 Rituximab has shown clinical activity in the treatment of B-cell lymphomas that are CD20+. Side effects include hypersensitivity reactions, hypotension, fevers, chills, rash, headache, and mild nausea and vomiting. 

Toremifene is an estrogen receptor antagonist. The pharmacokinetics of toremifene are best described by a two-compartment model, with an a half-life of 4 hours and an elimination half-life of 5 days. Peak plasma concentrations are achieved approximately 3 hours after an oral dose. Toremifene is metabolized extensively, with metabolites found primarily in the feces. Toremifene is used for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor-positive or unknown tumors. Toremifene causes hot flashes, vaginal bleeding, thromboembolism, and visual acuity changes. 

The original proposal of the approach, supported by a Monte Carlo simulation study [36], has been further validated with both pre-clinical [38, 39] and clinical studies [40]. It has been shown to be robust and accurate, and is not highly dependent on the models used to fit the data. The method can give poor estimates of absorption or bioavailability in two sets of circumstances (i) when the compound shows nonlinear pharmacokinetics, which may happen when the plasma protein binding is nonlinear, or when the compound has cardiovascular activity that changes blood flow in a concentration-dependent manner or (ii) when the rate of absorption is slow, and hence flip-flop kinetics are observed, i.e., when the apparent terminal half-life is governed by the rate of drug input. 

Ward et al. [125] investigated the disposition of 14C-radiolabeled primaquine in the isolated perfused rat liver preparation, after the administration of 0.5, 1.5, and 5 mg doses of the drug. The pharmacokinetics of primaquine in the experimental model was dependent on dose size. Increasing the dose from 0.5 to 5 mg produced a significant reduction in clearance from 11.6 to 2.9 mL/min. This decrease was accompanied by a disproportionate increase in the value of the area under the curve from 25.4 to 1128.6 pg/mL, elimination half-life from 33.2 to 413 min, and volume of distribution from 547.7 to 1489 mL. Primaquine exhibited dose dependency in its pattern of metabolism. While the carboxylic acid derivative of primaquine was not detected perfusate after the 0.5 mg dose, it was the principal perfusate metabolite after 5 mg dose. Primaquine was subject to extensive biliary excretion at all doses, the total amount of 14C-radioactivity excreted in the bile decreased from 60 to 30%i as the dose of primaquine was increased from 0.5 to 5 mg. 

Incorporation of fluorine at a site adjacent to a "metabolic soft spot" has also been used as a strategy to increase duration of action. Linopir-dine (24) was among the first clinical compounds that enhanced potassium-evoked release of acetylcholine in preclinical models of AD [22]. Linopirdine showed no clinical efficacy and its human pharmacokinetic profile was suggested as the reason for this lack of clinical efficacy. Specifically noted was the molecule s poor brain exposure and short half-life due to formation of the N-oxides 25 and 26 (Table 3) [23,24]. Optimization of 24 resulted in replacement of the indolone core by the anthracenone 27, which had improved in vitro activity, but still exhibited a short duration of action. To improve the metabolic stability, fluorine... 

No modern studies of the human pharmacokinetics of LSD have been done, largely because human experimentation has virtually stopped. An older study that used a spectrofluorometric technique for measuring plasma concentrations of LSD was done in humans given doses of 2 Mg/kg i.v. After equilibration had occurred in about 30 min, the plasma level was between 6 and 7 ng/ml. Subsequently, plasma levels gradually fell until only a small amount of LSD was present after 8 hr. The half-life of the drug in humans was calculated to be 175 min (2). Subsequent pharmacokinetic analysis of these data indicated that plasma concentrations of LSD were explained by a two-compartment open model. Performance scores were highly correlated with concentration in the tissue (outer) compartment, which was calculated at 11.5% of body weight. The new estimation of half-life for loss of LSD from plasma, based on this model, was 103 min (47). 

---