Dose-dependent Disposition Research Articles

Loncastuximab tesirine, an anti-CD19 antibody-drug conjugate, in relapsed/refractory B-cell acute lymphoblastic leukemia

AbstractRelapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) remains a therapeutic challenge. Loncastuximab tesirine is an antibody-drug conjugate against CD19, an antigen expressed in many B-cell malignancies. This open-label, single-arm, dose-escalation, dose-expansion study assessed the safety, tolerability, pharmacokinetics (PKs), immunogenicity, and preliminary clinical activity of loncastuximab tesirine in adults with R/R B-ALL. A total of 35 patients were enrolled, with a median age of 55 years (range, 20-80) and a median of 3 prior therapies (range, 1-15). All patients received at least 1 IV infusion of loncastuximab tesirine at 15 to 150 μg/kg once every 3 weeks (Q3W; n = 30) or 50 μg/kg IV weekly (n = 5). Common treatment-emergent adverse events (TEAEs) were nausea (42.9%), febrile neutropenia (37.1%), and reversible liver test abnormalities. Grade ≥3 TEAEs were reported in 85.7% patients, most commonly febrile neutropenia and other hematologic abnormalities and reversible liver test abnormalities. There were no treatment-related deaths. Four patients (11.4%) had grade 2 infusion-related reactions, and 1 patient (150 μg/kg Q3W) had a dose-limiting toxicity of hyperbilirubinemia that resolved within 6 days without further action. The maximum tolerated dose was not reached. Three patients achieved complete responses, 1 each at 30, 120, and 150 μg/kg Q3W. PK studies showed marked interpatient variability, with target-mediated drug disposition seeming to contribute to time- and dose-dependent disposition. No clinically relevant anti–drug-antibody formation occurred. The trial was terminated in the dose-escalation phase because of slow accrual. This trial was registered at www.clinicaltrials.gov as NCT02669264.

Dose-dependent plasma disposition kinetics of albendazole in goats

Dose-dependent plasma disposition kinetics of albendazole in goats

Pharmacokinetics and Hepatic Extraction of Recombinant Human Parathyroid Hormone, hPTH (1–34), in Rat, Dog, and Monkey

The pharmacokinetics (PK) and hepatic extraction (EH) of human PTH (1–34), hPTH (1–34), were characterized in rat, dog, and monkey, following intraportal (IPO) and intravenous (IV) bolus administration. hPTH (1–34) was administered to Sprague–Dawley rats (2, 10, 100 µg/kg), beagle dogs (3, 6 µg/kg), and rhesus monkeys (6, 30 µg/kg). Serum concentrations of immunoreactive hPTH (1–34) were used to derive PK parameters. IPO bioavailability (FIPO) was determined by comparing dose-normalized serum exposure (i.e., AUCIPO/AUCIV). EH was estimated as 1−FIPO. In all species, greater than dose-proportional increases in exposure (i.e., Cmax and AUC) were observed for both routes. Dose-dependent disposition (i.e., time-average clearance (CL) and half-life (t½) were observed in all three species. In rats, EH values of 71% (2 µg/kg), 35% (10 µg/kg), and <1% (100 µg/kg) were obtained. In dogs, EH values of 90% (3 µg/kg) and 66% (6 µg/kg) were obtained. In monkeys, EH values of 25% (6 µg/kg) and <1% (30 µg/kg) were observed. In conclusion, hPTH (1–34) is subject to hepatic first pass extraction in rat, dog, and monkey with evidence of saturation in the rat. Saturable hepatic extraction in dog and monkey is inconclusive due to the limited dose range investigated.

Regional oral absorption, hepatic first-pass effect, and non-linear disposition of salmon calcitonin in beagle dogs

The dose-dependent disposition, first pass hepatic elimination, and absorption pharmacokinetics (PK) of salmon calcitonin (sCT) were investigated in a canine Intestinal Vascular Access Port (IVAP) model. The PK of sCT were determined after intravenous (IV), subcutaneous (SC), portal venous (PV), and oral (PO) administration of sCT. Regional oral absorption of unformulated sCT was also evaluated by direct administration into the duodenum (ID), ileum (IL), and colon (IC) by means of surgically implanted, chronic catheters. Plasma samples were collected and analyzed by radioimmunoassay (RIA). Salmon calcitonin PK were evaluated using 2-compartmental and model independent methods. Intravenous sCT PK were non-linear over the dose range studied. High dose groups (100–1000 μg) demonstrated higher total plasma clearance (CL) and V dss than the low dose groups (1–25 μg). However, the MRT did not change for doses ranging from 10 to 1000 μg. After SC administration, the absorption of sCT was rapid with bioavailability (BA) varying from 21.4 to 52.9%. However, the BA of sCT was low after ID, IL, and IC administration (0.039, 0.064, and 0.021%, respectively). The role of hepatic first-pass elimination was negligible. The results of these studies demonstrate that the elimination of sCT is rapid but does not occur in the liver. Enhanced sCT clearance at higher doses was indicated by increasing V dss values, and it is hypothesized that increased renal blood flow and/or saturated plasma protein binding may contribute to the non-linear behavior. The IVAP canine model was found to have utility for probing the absorption and disposition PK of sCT. The combination of high oral bioavailability variability and non-linear disposition of sCT may produce highly variable therapeutic effects. The practical impact of the non-linear disposition of sCT remains to be determined. Based on the current results it appears that the rate-limiting step to the successful oral administration of sCT is its delivery into the portal vein since hepatic metabolism was negligible.

Dose-Dependent Disposition of Sodium Arsenate in Mice Following Acute Oral Exposure

Dose-Dependent Disposition of Sodium Arsenate in Mice Following Acute Oral Exposure. Hughes, M. F., Menache, M., and Thompson, D. J. (1994). Fundam. Appl. Toxicol. 22, 80-89.The effect of dose on arsenate disposition was studied in adult female B6C3F1 mice, dosed po with 0.5 to 5000 μg/kg [73As]arsenate in water. Urine was collected at 1, 2, 4, 8, 12, 24, and 48 hr and feces at 24 and 48 hr postexposure. The mice were euthanized at 48 hr and tissues were removed. Recovery of arsenate-derived radioactivity ranged from 83 to 89%; 66-79% of the dose was excreted in urine, 10-18% in feces, and <1% remained in the tissues. Although dose had no effect on the 48-hr excretion of radioactivity, the level of radioactivity in several tissues increased significantly with dose. The urine was analyzed for arsenic metabolites by using ion chromatography to analyze for arsenate, methylarsonic acid (MMA), and dimethylarsinic acid (DMA); ion-pairing high-performance liquid chromatography was used for arsenite analysis. Arsenate elimination ranged from 3 to 15%. DMA was the predominant metabolite excreted (51-64% of dose), but no effect of dose on its elimination was detected. As the dose of arsenate increased, the amount of MMA excreted (0.1-1.0% of dose) significantly increased. At 5000 μg/kg arsenate, a significant increase in arsenite excretion was observed. At doses of arsenate ⩽500 μg/kg, peak elimination of DMA occurred within 4 hr postexposure. At the 5000 μg/kg dose, DMA peak elimination shifted to 8 hr and a lower amount was excreted. In addition, at the 5000 μg/kg dose, there was an increase of arsenate and arsenite in the 1- and 2-hr urines. These results suggest that an acute dose of arsenate can affect the metabolism of arsenicals. High doses lead to the accumulation of intermediates that are more reactive than DMA, and this response may lead to increased toxicity.

Dose-Dependent Disposition of Sodium Arsenate in Mice Following Acute Oral Exposure

Dose-Dependent Disposition of Sodium Arsenate in Mice Following Acute Oral Exposure

Pharmacokinetics and pharmacodynamics of valproate analogs in rats. II. Pharmacokinetics of octanoic acid, cyclohexanecarboxylic acid, and 1‐methyl‐1‐cyclohexanecarboxylic acid

The pharmacokinetics of valproic acid (VPA) and three structural analogs, octanoic acid (OA), cyclohexanecarboxylic acid (CCA), and 1-methyl-1-cyclohexanecarboxylic acid (MCCA), were examined in female Sprague-Dawley rats. All four carboxylic acids evidenced dose-dependent disposition. A dose-related decrease in total body clearance was observed for each test compound, suggesting the presence of saturable elimination processes. Furthermore, the apparent volume of distribution for these compounds was, with the exception of CCA, dose-dependent, indicating that binding to proteins in serum and/or tissues may be saturable. Both VPA and MCCA exhibited enterohepatic recirculation, although the degree of recirculation appeared to be dose- and compound-dependent. Significant quantities of both VPA and MCCA were excreted in the urine as base-labile conjugates, presumably representing glucuronides. In contrast, OA and CCA were not excreted in the urine as base-labile conjugates and did not evidence enterohepatic recirculation. CCA displayed apparent Michaelis-Menten kinetics, although the calculated Km was dose-dependent. The results suggest that relatively minor changes in chemical structure have a marked influence on the metabolism and disposition of low molecular weight carboxylic acids.

Dose and sex-dependent disposition of ketoconazole in rats.

The disposition of the antifungal drug ketoconazole was studied in mature (60-day-old) male and female rats given single intravenous doses of 10, 20 or 40 mg/kg body weight. The plasma profiles of ketoconazole were characterized by an initial rapid decline, followed by an apparent zero-order decline and a subsequent first-order elimination phase. In male animals the zero-order phase was less pronounced, resulting in a 3-5 times higher overall rate of elimination. A consequence of the dose-dependent disposition was that a 4-fold increase in dose resulted in a 9- and 17-fold increase in the area under the plasma concentration-time curve (AUC) of females and males, respectively. Terminal half-lives were independent of dose in both sexes. The disproportionate increase in AUC with dose, together with the observation that no intact ketoconazole was excreted in urine and only very small amounts in bile (less than 1% of given dose), suggest that the dose-dependent disposition is caused by saturation of metabolizing enzymes. These enzymes are most likely under the influence of androgens, since the capacity of males to eliminate ketoconazole was reduced by castration and in females this capacity was increased by testosterone treatment.

Dose dependent disposition of sulphadimidine and of its N4‐acetyl and hydroxy metabolites in plasma and milk of dairy cows

The disposition of sulphadimidine (SDM) and of its N4-acetyl (N4-SDM) and two hydroxy metabolites, 6-hydroxymethyl-(SCH2OH) and 5-hydroxyasulphadimidine (SOH), was studied in plasma and milk of dairy cows following intramuscular or intravenous administration of sulphadimididine-33.3% at doses of 10, 45, 50, and 100 mg/kg. The main metabolite in plasma as well as in milk was SCH2OH. The metabolite percentages, the final plasma elimination half-lives, and the time of peak SDM concentrations in milk are presented for different dosages. The concentrations of SDM and its metabolites in milk ran parallel to those in plasma beyond 4 hours p.i. The metabolite concentrations in plasma and milk were lower than those of the parent SDM. Sulphate and glucuronide metabolites could not be detected in milk. At high doses (45 mg/kg or more) and SDM plasma concentrations exceeding 20 micrograms/ml, a capacity limited metabolism of SDM to SCH2OH was noticed, viz. a steady state concentration of SCH2OH and a biphasic elimination pattern for SDM and SCH2OH in plasma and milk. The mean ultrafiltrate ratios of the milk to plasma concentrations with respect to SDM, SCH2OH, SOH, and N4-SDM were: 0.69, 0.22, 020, and 0.63, respectively. The total amount of SDM and its metabolites recovered from the milk after milking twice daily over the whole experimental time was less than 2% of the applied dose. A bioassay method allowed of detecting qualitatively SDM concentrations exceeding 0.2 micrograms/ml in plasma or milk. Withholding times for edible tissues and milk are suggested.

Pharmacokinetic evidence for blood flow depression in dose dependent disposition of 4-aminoantipyrine in rabbits.

Pharmacokinetic relationships have been developed to characterize a one-compartment drug disposition model which includes perfusion limited elimination processes. The derived expressions have been applied to plasma concentration and urinary excretion data obtained after rapid intravenous administration of 4-aminoantipyrine to rabbits. The mathematical relationships and experimental data demonstrate that dose dependent disposition of 4-aminoantipyrine is a result of reduced renal and hepatic blood flow caused by the drug itself.

Dose-dependent disposition of fractionated 3H-heparin in rats.

To investigate the disposition of fractionated 3H-heparin, commercial 3H-heparin was fractionated by affinity chromatography on protamine-Sepharose and subsequently by Sephadex G-100 chromatography. Effect of dose on the disposition of fractionated 3H-heparin was studied. At an early stage following the intravenous administration of fractionated 3H-heparin which had either affinity or non-affinity for protamine-Sepharose, elimination of the radioactivity from plasma was delayed with increasing dose. Even at 5 h after the administration when most radioactivity in plasma disappeared, the cumulative urinary recovery was only 4.8 to 8.4% of dose (1 to 15 microCi/kg), and 61 to 43% of dose was found in liver. Therefore, it was suggested that tissue (liver) distribution of radioactivity might be a predominant factor for the dose-dependent disappearance of the radioactivity from plasma at an early stage following the administration of fractionated 3H-heparin. Plasma radioactivity levels tended to be pseudo-steady state or to increase slightly after about 1 to 2 h following the administration of fractionated 3H-heparin. Participation of entero-hepatic circulation in this tendency was rejected.

Ocular and systemic bioavailability of ophthalmic flurbiprofen.

Flurbiprofen, a nonsteroidal antiinflammatory agent which is not ocularly metabolized, was employed as a probe compound to investigate the drug kinetic relationship between systemic and ocular humoral circulation. The ocular and systemic bioavailabilities of topically applied flurbiprofen were also quantitated. Anesthetized albino female rabbits received flurbiprofen doses intracamerally, topically, and intravenously at 2 to 4 week intervals. Aqueous humor and plasma were used as the sampling compartments. Plasma clearance values of flurbiprofen were 6.77 and 7.87 ml/min, after 6-mg and 208-micrograms intravenous doses, respectively. These values were not significantly different and indicated no dose-dependent disposition kinetics over a 30-fold dose range. Both ocular and systemic flurbiprofen dispositions followed a biexponential pattern with a rapid distribution phase. The systemic and ocular distribution half-lives of flurbiprofen were 12 min and 15 min, respectively. The plasma elimination half-life was 74 min and the aqueous humor elimination half-life was 93 min. The latter approximated the turnover rate of aqueous humor and suggested that aqueous humor drainage was the major process of flurbiprofen elimination from the globe. About 99% of flurbiprofen is bound to plasma protein. At distribution equilibrium, the plasma and aqueous humor concentrations of flurbiprofen differed by a hundredfold, suggesting that only free drug entered the aqueous humor after the administration of a systemic dose. In the ophthalmic studies, right eyes were instilled with 50 microliters of 0.3% flurbiprofen in saline (dose = 150 micrograms), and left eyes were instilled with 50 microliters of 0.15% flurbiprofen in saline (dose = 75 micrograms). When the area of the aqueous humor concentration-versus-time curve values was normalized by the administration dose, the 75-micrograms dose was 30% more available to ocular tissues than was the 150-micrograms dose. This demonstrated a disproportionate relationship between the administered dose and the fraction absorbed. The intracameral dose was considered to be completely bioavailable for intraocular effects. The ocular bioavailability of the ophthalmic dose was defined by using intracameral administration as a standard measurement. The ocular bioavailabilities of the 75-micrograms and 150-micrograms topical flurbiprofen doses were 10% and 7%, respectively. Systemic bioavailability after topical administration of 225 micrograms of flurbiprofen was 74%.

Intravenous ampicillin pharmacokinetics in the third trimester of pregnancy.

The pharmacokinetics of a single dose of intravenous ampicillin were studied in nine patients during their third trimester of pregnancy. Each volunteer was given either 500 mg (5.7-8.8 mg/kg) or 1 g (15.4-21.4 mg/kg) of sodium ampicillin by rapid infusion. Postinfusion plasma concentration-time curves followed biexponential decay in all subjects. Calculated parameters included a mean plasma distribution volume of 177.1 +/- 97.5 ml/kg, tissue or peripheral distribution volume of 246.2 +/- 143.9 ml/kg, elimination half-life of 1.60 +/- 0.51 h, and total body clearance of 4.59 +/- 1.48 ml/min/kg. Dose-dependent disposition was not observed. Gestation-specific drug therapy research during pregnancy is discussed.

Dose-dependent disposition of n-hexane in F-344 rats after inhalation exposure

The purpose of this study was to assess the disposition of radioactivity in rats after single inhalation exposures to varying concentrations of [1,2- 14C]-n-hexane. Male Fischer 344 rats were exposed to 500, 1000, 3000 or 10,000 ppm 14C-n-hexane for 6 hr and the elimination of radioactivity followed for 72 hr after exposure. The disposition of radioactivity was dose-dependent, with 12, 24, 38 and 62% of the acquired body burden excreted as n-hexane by the lung with increasing exposure concentration. In contrast, 38, 31, 27 and 18% of the body burden of radioactivity was recovered as expired 14CO 2 and 35, 40, 31 and 18% was recovered in the urine with increasing n-hexane concentration. Radioactivity remaining in the tissues and carcass 72 hr after exposure represented 6.1, 8.8, 7.4 and 5.4% of the body burden for the respective exposures. The dose-dependent elimination of radioactivity was apparently due in part to an inhibition of n-hexane metabolism, reflected by a decrease in total 14CO 2 and urinary 14 C excretion after 10,000 ppm exposure compared to the 3000 ppm exposure.

Liposome Disposition in Vivo II: Dose Dependency

The dose-dependent disposition of extruded multilamellar (diameter ∼1 μm) negatively charged liposomes containing entrapped [14C]inulin was studied in mice. Mice received 1500, 300, or 15 μmoles of liposomal lipid/kg iv. Carbon 14 levels were measured in the blood, liver, spleen, and carcass for 72 hr. A pronounced saturation effect, consistent with the known dose behavior of other colloids, was seen at early times; it was manifested by higher dose values in the blood and spleen but by lower liver values as the dose increased. This dose effect was attenuated in the liver but was maintained in the spleen at later times, and percent dose values approached plateau values in all tissues for all doses at later times. [14C]Inulin was used as the liposomal marker because of its inability to enter cells (or, presumably, leave them if delivered there by liposomes) in its free form. An early decline in carbon 14 levels (over the first 48 hr) was seen in the liver for the low and medium doses. Because of the known ability of blood factors to cause liposomes to leak their contents, this decline was interpreted as being a loss of [14C]inulin from extracellularly bound liposomes during this period. Moreover, the plateau carbon 14 levels at later times were interpreted as approximating the true level of intracellular inulin delivery by the liposomes.

Pharmacokinetics of propranolol.

The pharmacokinetics of propranolol after the administration of 40, 80, and 120 mg p.o. and 10 mg i.v. was studied in nine healthy male volunteers. Propranolol was analyzed after extraction and derivatization by gas-liquid chromatography. A multiexponential curve-stripping program was used for the pharmacokinetic analysis. The volume of distribution was about 6 liters . kg-1, bioavailability around 25%, with a mean terminal half-life of 6 hr. There was no evidence of either dose dependent disposition kinetics or an oral threshold dose. A slight increase in urine volume was observed after propranolol administration.

Dose-dependent disposition of oral propranolol in normal subjects.

The pharmacokinetics and relative systemic availability or oral propranolol were studied in three healthy volunteers following administration of 10, 40, and 80 mg of propranolol hydrochloride. Plasma concentrations of propranolol were determined using a sensitive and specific fluorometric high pressure liquid chromatographic technique. In the dosage range studied, the amount of propranolol reaching the systemic circulation increased with dose, while half-lives remained unchanged. The apparent 'threshold dose' for propranolol was much smaller than previously reported, and its contribution to the observed dose-dependent availability is doubtful. Apparent intrinsic clearance values were shown to decrease with increase in dose, with a true maximal intrinsic clearance of 5.4 l kg-1 h-1. These data suggest the saturation of a low capacity enzyme system in the liver and are consistent with theoretical characteristics of a drug that is extensively metabolized during its first pass through the liver.

Disposition Kinetics of Griseofulvin in Dogs

Griseofulvin and its main metabolite, 6-demethylgriseofulvin (6-DMG), have been administered i.v. to dogs. The plasma data of griseofulvin were found to fit biexponential equations while the urinary excretion rate data of 6-DMG after its i.v. dose (and after griseofulvin administration) were found to fit triexponential equations. When increasing doses of griseofulvin were administered intravenously, some dogs followed dose-independent disposition kinetics, while others showed definite evidence of dose-dependent disposition kinetics. The distribution rate constants and the volume of distribution were found changed with dose in dogs showing dose-dependent disposition kinetics. However, the urinary recovery of the main metabolite, 6-DMG, remained almost constant. It is, therefore, postulated that the dose-dependent disposition kinetics of griseofulvin might be attributed to changes in tissue distribution rather than changes in the intrinsic metabolic activity.