Pharmacokinetic-pharmacodynamic Study Research Articles

Using real-world data to inform dosing strategies of rituximab for pediatric patients with frequent-relapsing or steroid-dependent nephrotic syndrome: a prospective pharmacokinetic-pharmacodynamic study.

Objectives: Rituximab is frequently used off-label for the treatment of frequent-relapsing/steroid-dependent nephrotic syndrome (FRNS/SDNS). However, the optimal dosing schedules remain undetermined. The objective of this study was to establish a population pharmacokinetic-pharmacodynamic (PK-PD) model in pediatric patients with FRNS/SDNS, and to investigate dosing regimens that provide adequate suppression of B lymphocytes. Methods: A prospective, open-label, single-center study was conducted in Nephrology Department at Children's Hospital of Fudan University, and a two-compartment PK model of rituximab in pediatric FRNS/SDNS has been developed previously by our group. CD19+ lymphocyte count profiles were obtained from these patients. The presence of anti-rituximab antibodies was assessed prior to medication in children who had previously received rituximab or during follow-up at the last sampling point for PK analysis. PK-PD analyses were performed to describe the changes of CD19+ lymphocytes, with rituximab assumed to increase their death rate. Monte Carlo simulation was conducted to evaluate different dosing regimens. Results: In total, 102 measurements of CD19+ lymphocyte counts were available for PK-PD analysis. No detectable levels of anti-rituximab antibodies were observed during the PK follow-up period. A turnover model with saturable stimulatory action of rituximab on the removal of lymphocytes best characterized the relationship between rituximab concentration and CD19+ lymphocyte counts, where the Emax and EC50 were estimated to be 99.6*106/L and 5.87μg/mL, respectively. Simulations indicated that a single infusion of 750mg/m2 and 2 infusions of 375mg/m2 both yielded a 10-week suppression of CD19+ lymphocytes. Conclusion: This study represents a first attempt to quantitatively describe the PK-PD relationship of rituximab in pediatric patients with FRNS/SDNS, and provide a potential pathway for future precision dosing strategy for rituximab therapy. Further clinical studies are warranted to evaluate the efficacy and safety of different dosing schemes.

Abstract B172: Potent anti-tumor activity of a selective and orally bioavailable reversible covalent CDK12 inhibitor

Abstract Cyclin-dependent kinase 12 (CDK12), in association with Cyclin K (CycK), regulates the elongation of transcription by modifying RNA polymerase II (RNAP II) through phosphorylation at Serine 2 (pS2) in the C-terminal domain, CDK12 plays an important role in maintaining genomic stability by modulating crucial cellular processes such as DNA damage response, splicing, and pre-mRNA processing. Overexpression of CDK12 has been observed in various tumor types, suggesting its potential oncogenic properties like other kinases involved in transcription. Given its significance in transcription and RNA processing, CDK12 has emerged as a promising therapeutic target for cancer treatment. We have identified a highly potent and selective reversible covalent inhibitor of CDK12, AU-22880, which exhibits significant anti-proliferative activity across various cancer cell lines. The covalent mode of action and on-target activity of AU-22880 were confirmed in a CDK12 target engagement assay and selective pS2 RNAPII inhibition respectively in a cellular context. Additionally, it has shown synergistic activity in combination with several standard-of-care agents in breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer cell lines. AU-22880 shows desirable ADME-PK properties and demonstrates excellent anti-tumor activity in xenograft models. In the HCC-70 TNBC xenograft model, AU-22880 demonstrated anti-tumor efficacy at well-tolerated doses. A pharmacokinetic-pharmacodynamic (PK-PD) study revealed dose-dependent target engagement, as evidenced by the inhibition of pS2 RNAPII and DNA damage repair (DDR) genes. Furthermore, AU-22880 exhibited good tolerability in rodents, dog, and monkeys at exposure levels that demonstrated efficacy. Efficacy of AU-22880 in combination with approved SOCs targeting DDR pathway are currently being investigated. The findings reported here highlight the promising therapeutic potential of AU-22880, both as a monotherapy and in combination with existing treatments for the treatment of cancers characterized by DDR dysregulation. Citation Format: Leena Khare, Ramulu Poddutoori, Subhendu Mukherjee, Samiulla DS, Devaraja TS, Sivapriya Marappan, Shilpa Nayak, Sasirekha Sivakumar, Lakshmi Kaza, Suraj Tgore, Amit Dhudashiya, Raghavendra NR, Bhargav Gunnepalli, Aravind A B, Amith A, Charamanna KB, Thomas Antony, Kavitha Nellore, Girish Daginakatte, Shekar Chelur, Sanjeev Giri, Murali Ramachandra, Susanta Samajdar. Potent anti-tumor activity of a selective and orally bioavailable reversible covalent CDK12 inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B172.

Gut microbiota-based pharmacokinetic-pharmacodynamic study and molecular mechanism of specnuezhenide in the treatment of colorectal cancer targeting carboxylesterase

Specnuezhenide (SNZ) is among the main components of Fructus Ligustri Lucidi, which has anti-inflammation, anti-oxidation, and anti-tumor effect. The low bioavailability makes it difficult to explain the mechanism of pharmacological effect of SNZ. In this study, the role of the gut microbiota in the metabolism and pharmacokinetics characteristics of SNZ as well as the pharmacological meaning were explored. SNZ can be rapidly metabolized by the gut microbiome, and two intestinal bacterial metabolites of SNZ, salidroside and tyrosol, were discovered. In addition, carboxylesterase may be the main intestinal bacterial enzyme that mediates its metabolism. At the same time, no metabolism was found in the incubation system of SNZ with liver microsomes or liver homogenate, indicating that the gut microbiota is the main part involved in the metabolism of SNZ. In addition, pharmacokinetic studies showed that salidroside and tyrosol can be detected in plasma in the presence of gut microbiota. Interestingly, tumor development was inhibited in a colorectal tumor mice model administered orally with SNZ, which indicated that SNZ exhibited potential to inhibit tumor growth, and tissue distribution studies showed that salidroside and tyrosol could be distributed in tumor tissues. At the same time, SNZ modulated the structure of gut microbiota and fungal group, which may be the mechanism governing the antitumoral activity of SNZ. Furthermore, SNZ stimulates the secretion of short-chain fatty acids by intestinal flora in vitro and in vivo. In the future, targeting gut microbes and the interaction between natural products and gut microbes could lead to the discovery and development of new drugs.

Proteinuria and Exposure to Eculizumab in Atypical Hemolytic Uremic Syndrome.

Eculizumab is a monoclonal antibody for the treatment of atypical hemolytic uremic syndrome (aHUS). Kidney damage, a common condition in patients with aHUS, may result in proteinuria. Because proteinuria may affect the pharmacokinetics of therapeutic proteins such as eculizumab, the aim of our study was to investigate the effect of proteinuria on eculizumab pharmacokinetics. This study was an ancillary study of a previously performed pharmacokinetic-pharmacodynamic study of eculizumab in aHUS. Proteinuria, measured as urinary protein-creatinine ratios (UPCR), was investigated as covariate for eculizumab clearance. Thereafter, we evaluated the effect of proteinuria on the exposure to eculizumab in a simulation study for the initial phase and for a 2-weekly and 3-weekly interval in the maintenance phase. The addition of UPCR as a linear covariate on clearance to our base model resulted in a statistically improved fit ( P < 0.001) and reduction of unexplained variability in clearance. From our data, we predicted that in the initial phase, 16% of the adult patients with severe proteinuria (UPCR >3.1 g/g) will have inadequate complement inhibition (classical pathway activity >10%) on day 7 of treatment, compared with 3% of the adult patients without proteinuria. None of the pediatric patients will have inadequate complement inhibition at day 7 of treatment. For the 2- and 3-weekly dosing intervals, we predicted that, respectively, 18% and 49% of the adult patients and, respectively, 19% and 57% of the pediatric patients with persistent severe proteinuria will have inadequate complement inhibition, compared with, respectively, 2% and 13% of the adult patients and, respectively, 4% and 22% of the pediatric patients without proteinuria. Severe proteinuria is associated with a higher risk of underexposure to eculizumab. CUREiHUS, Dutch Trial Register, NTR5988/NL5833.

FORWARDS-1: an adaptive, single-blind, placebo-controlled ascending dose study of acute baclofen on safety parameters in opioid dependence during methadone-maintenance treatment—a pharmacokinetic-pharmacodynamic study

BackgroundTreatment of opiate addiction with opiate substitution treatment (e.g. methadone) is beneficial. However, some individuals desire or would benefit from abstinence but there are limited options to attenuate problems with opiate withdrawal. Preclinical and preliminary clinical evidence suggests that the GABA-B agonist, baclofen, has the desired properties to facilitate opiate detoxification and prevent relapse. This study aims to understand whether there are any safety issues in administering baclofen to opioid-dependent individuals receiving methadone.MethodsOpiate-dependent individuals (DSM-5 severe opioid use disorder) maintained on methadone will be recruited from addiction services in northwest London (NHS and third sector providers). Participants will be medically healthy with no severe chronic obstructive pulmonary disease or type 2 respiratory failure, no current dependence on other substances (excluding nicotine), no current severe DSM-5 psychiatric disorders, and no contraindications for baclofen or 4800 IU vitamin D (placebo). Eligible participants will be randomised in a 3:1 ratio to receive baclofen or placebo in an adaptive, single-blind, ascending dose design. A Bayesian dose-escalation model will inform the baclofen dose (10, 30, 60, or 90 mg) based on the incidence of ‘dose-limiting toxicity’ (DLT) events and participant-specific methadone dose. A range of respiratory, cardiovascular, and sedative measures including the National Early Warning Score (NEWS2) and Glasgow Coma Scale will determine DLT. On the experimental day, participants will consume their usual daily dose of methadone followed by an acute dose of baclofen or placebo (vitamin D3) ~ 1 h later. Measures including oxygen saturation, transcutaneous CO2, respiratory rate, QTc interval, subjective effects (sedation, drug liking, craving), plasma levels (baclofen, methadone), and adverse events will be obtained using validated questionnaires and examinations periodically for 5 h after dosing.DiscussionStudy outcomes will determine what dose of baclofen is safe to prescribe to those receiving methadone, to inform a subsequent proof-of-concept trial of the efficacy baclofen to facilitate opiate detoxification. To proceed, the minimum acceptable dose is 30 mg of baclofen in patients receiving ≤ 60 mg/day methadone based on the clinical experience of baclofen’s use in alcoholism and guidelines for the management of opiate dependence.Trial registrationClinicaltrials.gov NCT05161351. Registered on 16 December 2021.

A pharmacokinetic-pharmacodynamic study to elucidate the cardiovascular protective constituents in Danhong Injection

Danhong Injection (DHI) is one of the most popular Chinese medicine formulations to treat cardiovascular diseases. However, the effective components of DHI have not been well addressed. In the present study, a pharmacokinetics-pharmacodynamics (PK-PD) approach was employed to elucidate the effective compounds of DHI for the first time. Firstly, the cardiovascular protective effect of DHI was demonstrated on an adrenaline-induced acute blood stasis rat model by echocardiography and histopathology. Secondly, the levels of four blood stasis-related cytokines in plasma were examined by ELISA. Thirdly, the plasma concentrations of 10 compounds in DHI were determined using UHPLC-Q-Orbitrap-MS. Finally, PK-PD profiles were established to describe the relationship between compound concentrations and cytokine levels in plasma at 0–12 h following DHI administration. The results showed that DHI attenuated cardiovascular injury and regulated IL-2, cTnT, VEGF, and VEGFR-1. Except for the endogenous metabolites cytidine and uridine, danshensu, rosmarinic acid, and salvianolic acid B exhibited the highest plasma exposure. PK-PD correlation analysis indicated that concentrations of salvianolic acid A, caffeic acid, and ferulic acid were negatively correlated with the level of cTnT, while the concentration of salvianolic acid A was negatively correlated with the level of IL-2. These compounds may contribute to the cardiovascular protective effect of DHI.

Pharmacokinetic-Pharmacodynamic Study of Ampicillin-Cloxacillin Combination in Indian Thoroughbred Horses (Equus caballus) and Safety Evaluation of the Computed Dosage Regimen

The pharmacokinetics of ampicillin-cloxacillin, given as single intravenously dose of 10 mg.kg−1 (5 mg.kg−1 of ampicillin plus 5 mg.kg−1 of cloxacillin) was examined in clinically presented Indian thoroughbred horses (n = 6) in order to design appropriate dosing strategies. Drug concentrations in plasma were determined by high performance liquid chromatography (HPLC) and pharmacokinetic parameters were derived by non-compartmental analysis using WinNonlin software. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of ampicillin-cloxacillin against quality control strains of Escherichia coli and Staphylococcus aureus, grown in Muller Hinton Broth, were determined by broth microdilution method. For ampicillin, area under plasma drug concentration time curve (AUC) was 15.2 ± 0.54 µg.h.ml−1, mean residence time (MRT) was 1.33 ± 0.06 h and clearance (Cl) was 0.33 ± 0.01 L.h−1.kg−1. For cloxacillin, AUC was 18.0 ± 0.9 µg.h.ml−1, MRT was 1.28 ± 0.02 h and Cl was 0.28 ± 0.01 L.h−1.kg−1. MIC of ampicillin-cloxacillin combination against E. coli and S. aureus was determined to be 0.4 µg.ml−1. PK-PD integration indicated that to maintain %T > MIC value 50% for bacteria with MIC ≤ 0.4 µg.ml−1, an appropriate intravenous dosage regimen of ampicillin-cloxacillin combination in horses would be 15 mg.kg−1 (i.e. 7.5 mg.kg−1 of ampicillin plus 7.5 mg.kg−1 of cloxacillin), to be repeated at 12 h intervals. Safety profile of the recommended regimen did not significantly alter any of the 16 biochemical or haematological parameters studied.

Pharmacogenetics may explain part of the interindividual variability of dobutamine pharmacodynamics in neonates.

To determine whether the known single nucleotide polymorphisms in adrenoreceptor associated genes affect the haemodynamic response to dobutamine in critically ill neonates. Alleles in the known genetic single nucleotide polymorphisms in β1- and β2-adrenoceptor (AR) genes and Gs protein α-subunit gene (GNAS) possibly affecting inotropic effect were identified in patients of neonatal dobutamine pharmacokinetic-pharmacodynamic study. Linear mixed-effect models were used to describe the effect of genetic polymorphisms to heart rate (HR), left ventricular output (LVO) and right ventricular output (RVO) during dobutamine treatment. Twenty-six neonates (5 term, 21 preterm) were studied. Dobutamine plasma concentration and exposure time respective HR (adjusted to gestational age) is dependent on β1-AR Arg389Gly polymorphism so that in G/G (Gly) homozygotes and G/C heterozygotes dobutamine increases HR more than in C/C (Arg) homozygotes, with parameter estimate (95% CI) of 38.3 (15.8-60.7) beats/min per AUC of 100 μg L-1 h, P = .0008. LVO (adjusted to antenatal glucocorticoid administration and illness severity) and RVO (adjusted to gestational age and illness severity) is dependent on GNAS c.393C > T polymorphism so that in T/T homozygotes and C/T heterozygotes but not in C/C homozygotes LVO and RVO increase with dobutamine treatment, 24.5 (6.2-42.9) mL kg-1 min-1 per AUC of 100 μg L-1 h, P = .0095 and 33.2 (12.1-54.3) mL kg-1 min-1 per AUC of 100 μg L-1 h, P = .0025, respectively. In critically ill neonates, β1-AR Arg389Gly and GNAS c.393C > T polymorphisms may play a role in the haemodynamic response to dobutamine during the first hours and days of life.

Race and sex associations with tacrolimus pharmacokinetics in stable kidney transplant recipients.

Study ObjectiveThis study investigated race and sex differences in tacrolimus pharmacokinetics and pharmacodynamics in stable kidney transplant recipients.Design and SettingA cross‐sectional, open‐label, single center, 12‐h pharmacokinetic‐pharmacodynamic study was conducted. Tacrolimus pharmacokinetic parameters included area under the concentration‐time curve (AUC0–12), AUC0–4, 12‐h troughs (C 12 h), maximum concentrations (C max), oral clearance (Cl), with dose‐normalized AUC0–12, troughs, and C max with standardized adverse effect scores. Statistical models were used to analyze end points with individual covariate‐adjustment including clinical factors, genotypic variants CYP3A5*3, CYP3A5*6, CYP3A5*7(CYP3A5*3*6*7) metabolic composite, and ATP binding cassette gene subfamily B member 1 (ABCB1) polymorphisms.Patients65 stable, female and male, Black and White kidney transplant recipients receiving tacrolimus and mycophenolic acid ≥6 months post‐transplant were evaluated.Measurements and Main ResultsBlack recipients exhibited higher tacrolimus AUC0–12 (Race: p = 0.005), lower AUC* (Race: p < 0.001; Race × Sex: p = 0.068), and higher Cl (Race: p < 0.001; Sex: p = 0.066). Greater cumulative (Sex: p < 0.001; Race × Sex: p = 0.014), neurologic (Sex: p = 0.021; Race × Sex: p = 0.005), and aesthetic (Sex: p = 0.002) adverse effects were found in females, with highest scores in Black women. In 84.8% of Black and 68.8% of White patients, the target AUC0–12 was achieved (p = 0.027). In 31.3% of White and 9.1% of Black recipients, AUC0–12 was <100 ng‧h/ml despite tacrolimus troughs in the target range (p = 0.027). The novel CYP3A5*3*6*7 metabolic composite was the significant covariate accounting for 15%–19% of tacrolimus variability in dose (p = 0.002); AUC0–12 h* (p < 0.001), and Cl (p < 0.001).ConclusionsTacrolimus pharmacokinetics and adverse effects were different among stable kidney transplant recipient groups based upon race and sex with interpatient variability associated with the CYP3A5*3*6*7 metabolic composite. More cumulative, neurologic, and aesthetic adverse effects were noted among females. Tacrolimus regimens that consider race and sex may reduce adverse effects and enhance allograft outcomes by facilitating more patients to achieve the targeted AUC0–12 h.

Pharmacokinetic-Pharmacodynamic Study of Ampicillin-Cloxacillin Combination in Indian Thoroughbred Horses (Equus Caballus) and Safety Evaluation of the Computed Dosage Regimen

Pharmacokinetic-Pharmacodynamic Study of Ampicillin-Cloxacillin Combination in Indian Thoroughbred Horses (Equus Caballus) and Safety Evaluation of the Computed Dosage Regimen

Pharmacokinetics and Pharmacodynamics of Lysergic Acid Diethylamide Microdoses in Healthy Participants.

"Microdoses" of lysergic acid diethylamide (LSD) are used recreationally to enhance mood and cognition. Increasing interest has also been seen in developing LSD into a medication. Therefore, we performed a pharmacokinetic-pharmacodynamic study using very low doses of LSD. Single doses of LSD base (5, 10, and 20µg) and placebo were administered in a double-blind, randomized, placebo-controlled crossover study in 23 healthy participants. Test days were separated by at least 5days. Plasma levels of LSD and subjective effects were assessed up to 6hours after administration. Pharmacokinetic parameters were determined using compartmental modeling. Concentration-subjective effect relationships were described using pharmacokinetic-pharmacodynamic modeling. Mean (95% confidence interval) maximal LSD concentrations were 151pg/mL (127-181), 279pg/mL (243-320), and 500pg/mL (413-607) after 5, 10, and 20µg LSD administration, respectively. Maximal concentrations were reached after 1.1hours. The mean elimination half-life was 2.7hours (1.5-6.2). The 5µg dose of LSD elicited no significant acute subjective effects. The 10µg dose of LSD significantly increased ratings of "under the influence" and "good drug effect" compared with placebo. These effects began an average of 1.1hours after 10µg LSD administration, peaked at 2.5hours, and ended at 5.1hours. The 20µg dose of LSD significantly increased ratings of "under the influence," "good drug effects," and "bad drug effects." LSD concentrations dose-proportionally increased at doses as low as 5-20µg and decreased with a half-life of 3hours. The threshold dose of LSD base for psychotropic effects was 10µg.

Sedation With Midazolam After Cardiac Surgery in Children With and Without Down Syndrome: A Pharmacokinetic-Pharmacodynamic Study.

To compare the pharmacokinetics and pharmacodynamics of IV midazolam after cardiac surgery between children with and without Down syndrome. Prospective, single-center observational trial. PICU in a university-affiliated pediatric teaching hospital. Twenty-one children with Down syndrome and 17 without, 3-36 months, scheduled for cardiac surgery with cardiopulmonary bypass. Postoperatively, nurses regularly assessed the children's pain and discomfort with the validated COMFORT-Behavioral scale and Numeric Rating Scale for pain. A loading dose of morphine (100 µg/kg) was administered after coming off bypass; thereafter, morphine infusion was commenced at 40 µg/kg/hr. Midazolam was started if COMFORT-Behavioral scale score of greater than 16 and Numeric Rating Scale score of less than 4 (suggestive of undersedation). Plasma midazolam and metabolite concentrations were measured for population pharmacokinetic- and pharmacodynamic analysis using nonlinear mixed effects modeling (NONMEM) (Version VI; GloboMax LLC, Hanover, MD) software. Twenty-six children (72%) required midazolam postoperatively (15 with Down syndrome and 11 without; p = 1.00). Neither the cumulative midazolam dose (p = 0.61) nor the time elapsed before additional sedation was initiated (p = 0.71), statistically significantly differed between children with and without Down syndrome. Population pharmacokinetic and pharmacodynamics analysis revealed no statistically significant differences between the children with and without Down syndrome. Bodyweight was a significant covariate for the clearance of 1-OH-midazolam to 1-OH-glucuronide (p = 0.003). Pharmacodynamic analysis revealed a marginal effect of the midazolam concentration on the COMFORT-Behavioral score. The majority of children with and without Down syndrome required additional sedation after cardiac surgery. This pharmacokinetic and pharmacodynamic analysis does not provide evidence for different dosing of midazolam in children with Down syndrome after cardiac surgery.

Population Pharmacokinetics and Pharmacodynamics Modeling of Torasemide and Furosemide After Oral Repeated Administration in Healthy Dogs.

Torasemide is a loop diuretic licensed in dogs for cardiogenic pulmonary oedema. The aim of this pharmacokinetic-pharmacodynamic (PK/PD) study was to define an optimally effective dosage regimen based on preclinical data. In a first study, 5 dogs received once-daily oral torasemide (0, 0.1, 0.2, 0.4, 0.8 mg/kg/day) for 14 days. A second study compared once-daily oral torasemide (0, 0.1, 0.2, 0.3, 0.4 mg/kg/day) to twice-daily furosemide (1, 2, 4, 8 mg/kg/day). For all doses of the second study, 11 dogs received a first day of treatment, followed by a 3 day washout and resumed daily treatment for 10 days (until Day 14). Blood and urine were collected to measure urinary torasemide excretion and plasma torasemide concentrations and daily diuresis and natriuresis. Torasemide PK was linear. After rapid absorption (Tmax 0.5–1 h), 61% of the bioavailable torasemide was eliminated unchanged in urine. Diuresis and natriuresis observed with torasemide were similar to the ones obtained after furosemide (daily dose-ratios: 1/20 to 1/10). The average diuresis increased from baseline (220 ± 53 mL/day for 10 kg dogs) to 730 ±120 mL after the first torasemide administration and up to 1150 ± 252 mL after 10 administrations at the highest dose. At higher doses (≥0.3 mg/kg/day), daily diureses after 10 diuretic treatment-days were higher than Day 1 and variable between dogs; in contrast, diureses remained constant over time and less variable for doses up to 0.2 mg/kg/day. Natriuresis peaked after the first day and decreased dramatically after the 2nd treatment-day then stabilized to a value close to baseline, except for 0.4 mg/kg/day. Urinary torasemide excretion predicted pharmacodynamics better than plasma concentrations. The decrease in natriuresis observed was successfully modeled using a resistance mechanism; this is likely due to a reabsorption of sodium which did not seem however to affect the volume of urine excreted. For a daily target diuresis of 460 mL/dog/day in severe pulmonary oedema (net fluid loss 240 mL/dog/day), a computed dose of 0.26 mg/kg/day (3.5 mg/kg/day furosemide-equivalent) was selected for clinical studies. Due to high inter-individual variability in diureses at doses ≥0.3 mg/kg, higher doses should be limited to 3–5 days to avoid supra-clinical effects in high responders.

Allopregnanolone Pharmacokinetic-Pharmacodynamic Modeling and Simulations in Dogs with Naturally-Occurring Epilepsy

Allopregnanolone (ALLO), a neurosteroid that positively modulates synaptic and extrasynaptic GABAA receptors, may be useful as a first-line treatment for human and canine status epilepticus (SE). We completed an IV and IM ALLO pharmacokinetic-pharmacodynamic (PKPD) study in dogs. The objectives of this work were: 1) build a PKPD model relating plasma ALLO concentrations to electroencephalographic (EEG) activity, and 2) simulate EEG effects of IV and IM ALLO doses.

Analgesic and Respiratory Depressant Effects of R-dihydroetorphine: A Pharmacokinetic-Pharmacodynamic Analysis in Healthy Male Volunteers.

There is an ongoing need for potent opioids with less adverse effects than commonly used opioids. R-dihydroetorphine is a full opioid receptor agonist with relatively high affinity at the μ-, δ- and κ-opioid receptors and low affinity at the nociception/orphanin FQ receptor. The authors quantified its antinociceptive and respiratory effects in healthy volunteers. The authors hypothesized that given its receptor profile, R-dihydroetorphine will exhibit an apparent plateau in respiratory depression, but not in antinociception. The authors performed a population pharmacokinetic-pharmacodynamic study (Eudract registration No. 2009-010880-17). Four intravenous R-dihydroetorphine doses were studied: 12.5, 75, 125, and 150 ng/kg (infused more than 10 min) in 4 of 4, 6 of 6, 6 of 6, and 4 of 4 male subjects in pain and respiratory studies, respectively. The authors measured isohypercapnic ventilation, pain threshold, and tolerance responses to electrical noxious stimulation and arterial blood samples for pharmacokinetic analysis. R-dihydroetorphine displayed a dose-dependent increase in peak plasma concentrations at the end of the infusion. Concentration-effect relationships differed significantly between endpoints. R-dihydroetorphine produced respiratory depression best described by a sigmoid EMAX-model. A 50% reduction in ventilation in between baseline and minimum ventilation was observed at an R-dihydroetorphine concentration of 17 ± 4 pg/ml (median ± standard error of the estimate). The maximum reduction in ventilation observed was at 33% of baseline. In contrast, over the dose range studied, R-dihydroetorphine produced dose-dependent analgesia best described by a linear model. A 50% increase in stimulus intensity was observed at 34 ± 11 pg/ml. Over the dose range studied, R-dihydroetorphine exhibited a plateau in respiratory depression, but not in analgesia. Whether these experimental advantages extrapolate to the clinical setting and whether analgesia has no plateau at higher concentrations than investigated requires further studies.

Downregulation of ABCB1 gene in patients with total hip or knee arthroplasty influences pharmacokinetics of rivaroxaban: a population pharmacokinetic-pharmacodynamic study.

Rivaroxaban is a substrate for ABCB1 transporter and is commonly used in patients undergoing hip or knee replacement surgery for thromboprophylaxis. The objective of this study was to develop a population pharmacokinetic-pharmacodynamic (PK-PD) model to investigate the influence of ABCB1 gene expression and polymorphism on rivaroxaban exposure and anticoagulation effects. Five blood samples per patient were collected during 5days after the surgery for the determination of rivaroxaban concentration in plasma and for determination of prothrombin time and partial thromboplastin time. Non-linear mixed effects model was used for a population PK-PD analysis and for testing covariate effects. A one-compartment PK model with first-order absorption adequately described the pharmacokinetic data. The typical oral clearance (CL/F) was 6.12L/h (relative standard error, 15.8%) and was associated with ABCB1 expression. Compared to base line before the surgery, a significant ABCB1 downregulation was observed 5days after the surgery (p < 0.001). Prothrombin time and partial thromboplastin time were both linearly associated to the logarithm of the rivaroxaban plasma concentration. We confirmed that variable rivaroxaban CL/F is associated with ABCB1 expression, which is in accordance with previous studies on P-glycoprotein involvement in rivaroxaban PK. Furthermore, we observed the downregulation of ABCB1 expression after the surgery. The cause remains unclear and further research is needed to explain the underlying mechanisms.

The impact of tacrolimus exposure on extrarenal adverse effects in adult renal transplant recipients.

Tacrolimus has been associated with notable extrarenal adverse effects (AEs), which are unpredictable and impact patient morbidity. The association between model-predicted tacrolimus exposure metrics and standardized extrarenal AEs in stable renal transplant recipients was investigated and a limited sampling strategy (LSS) was developed to predict steady-state tacrolimus area under the curve over a 12-h dosing period (AUCss,0-12h ). All recipients receiving tacrolimus and mycophenolic acid ≥6months completed a 12-h cross-sectional observational pharmacokinetic-pharmacodynamic study. Patients were evaluated for the presence of individual and composite gastrointestinal, neurological, and aesthetic AEs during the study visit. The associations between AEs and tacrolimus exposure metrics generated from a published population pharmacokinetic model were investigated using a logistic regression analysis in NONMEM 7.3. An LSS was determined using a Bayesian estimation method with the same patients. Dose-normalized tacrolimus AUCss,0-12h and apparent clearance were independently associated with diarrhoea, dyspepsia, insomnia and neurological AE ratio. Dose-normalized tacrolimus maximum concentration was significantly correlated with skin changes and acne. No AE associations were found with trough concentrations. Using limited sampling at 0, 2h; 0, 1, 4h; and 0, 1, 2, 4h provided a precise and unbiased prediction of tacrolimus AUC (root mean squared prediction error <10%), which was not well characterized using trough concentrations only (root mean squared prediction error >15%). Several AEs (i.e. diarrhoea, dyspepsia, insomnia and neurological AE ratio) were associated with tacrolimus dose normalized AUCss,0-12h and clearance. Skin changes and acne were associated with dose-normalized maximum concentrations. To facilitate clinical implementation, a LSS was developed to predict AUCss,0-12h values using sparse patient data to efficiently assess projected immunosuppressive exposure and potentially minimize AE manifestations.

Is tranexamic acid exposure related to blood loss in hip arthroplasty? A pharmacokinetic-pharmacodynamic study.

Tranexamic acid (TXA) is an antifibrinolytic agent, decreasing blood loss in hip arthroplasty. The present study investigated the relationship between TXA exposure markers, including the time above the in vitro threshold reported for inhibition of fibrinolysis (10mg l-1 ), and perioperative blood loss. Data were obtained from a prospective, double-blind, parallel-arm, randomized superiority study in hip arthroplasty. Patients received a preoperative intravenous bolus of TXA 1g followed by a continuous infusion of either TXA 1g or placebo over 8h. A population pharmacokinetic study was conducted to quantify TXA exposure. In total, 827 TXA plasma concentrations were measured in 166 patients. A two-compartment model fitted the data best, total body weight determining interpatient variability in the central volume of distribution. Creatinine clearance accounted for interpatient variability in clearance. At the end of surgery, all patients had TXA concentrations above the therapeutic target of 10mg l-1 . The model-estimated time during which the TXA concentration was above 10mg l-1 ranged from 3.3h to 16.3h. No relationship was found between blood loss and either the time during which the TXA concentration exceeded 10mg l-1 or the other exposure markers tested (maximum plasma concentration, area under the concentration-time curve). In hip arthroplasty, TXA plasma concentrations were maintained above 10mg l-1 during surgery and for a minimum of 3h with a preoperative TXA dose of 1g. Keeping TXA concentrations above this threshold up to 16h conferred no advantage with regard to blood loss.

Population Pharmacokinetic Analyses of Lithium: A Systematic Review.

Even though lithium has been used for the treatment of bipolar disorder for several decades, its toxicities are still being reported. The major limitation in the use of lithium is its narrow therapeutic window. Several methods have been proposed to predict lithium doses essential to attain therapeutic levels. One of the methods used to guide lithium therapy is population pharmacokinetic approach which accounts for inter- and intra-individual variability in predicting lithium doses. Several population pharmacokinetic studies of lithium have been conducted. The objective of this review is to provide information on population pharmacokinetics of lithium focusing on nonlinear mixed effect modeling approach and to summarize significant factors affecting lithium pharmacokinetics. A literature search was conducted from PubMed database from inception to December, 2016. Studies conducted in humans, using lithium as a study drug, providing population pharmacokinetic analyses of lithium by means of nonlinear mixed effect modeling, were included in this review. Twenty-four articles were identified from the database. Seventeen articles were excluded based on the inclusion and exclusion criteria. A total of seven articles were included in this review. Of these, only one study reported a combined population pharmacokinetic-pharmacodynamic model of lithium. Lithium pharmacokinetics were explained using both one- and two-compartment models. The significant predictors of lithium clearance identified in most studies were renal function and body size. One study reported a significant effect of age on lithium clearance. The typical values of lithium clearance ranged from 0.41 to 9.39L/h. The magnitude of inter-individual variability on lithium clearance ranged from 12.7 to 25.1%. Only two studies evaluated the models using external data sets. Model methodologies in each study are summarized and discussed in this review. For future perspective, a population pharmacokinetic-pharmacodynamic study of lithium is recommended. Moreover, external validation of previously published models should be performed.

HPLC-PDA METHOD FOR THE QUANTIFICATION OF PARACETAMOL IN PLASMA: APPLICATION TO PK/PD STUDIES WITH ARTHRITIC RATS

Objective: To develop and validate an easy, rapid, sensitive and selective high-performance liquid chromatography with photodiode diode-array (HPLC-PDA) detection method for quantification of paracetamol and to demonstrate its application in a pharmacokinetic–pharmacodynamic study with arthritic rats.Methods: Paracetamol was separated from plasma samples (50-100 µl) by a single protein precipitation step, prior to HPLC-PDA detection. The separation was performed on a Knauer Eurospher II, C18 column 5 µm, 150 × 4.6 mm. The mobile phase comprised a mixture of water: methanol (75:25) and the flow rate was 1.1 ml/min. The detection wavelength was set at 245 nm. All analyses were carried out at room temperature (25 °C). Pharmacodynamics data were obtained with a gout-type pain model in rats.Results: The method was linear within a range of 0.2-200 µg/ml (R2≥0.99). The intra-day and inter-day precision and accuracy expressed as coefficient of variation and relative error, respectively were below 10%. The lower limit of quantification was 0.2 µg/ml. Plasma samples were stable at least for 5 w at ‒20° C.Conclusion: The validated method is sensitive, precise, accurate and specific as other more complex high-performance liquid chromatographic methods coupled to mass spectrometry (HPLC-MS), using small plasma samples (50-100 µl) and with a short time analysis (&lt;5 min). The method was successfully applied to a pharmacokinetic-pharmacodynamic study of paracetamol in arthritic rats.