Publications by authors named "Amit Khatri"

67 Publications

A rare case of Dandy-Walker syndrome in the 12-year-old girl.

J Indian Soc Pedod Prev Dent 2020 Jan-Mar;38(1):94-96

Department of Pedodontics and Preventive Dentistry, University College of Medical Sciences (University of Delhi) and GTB Hospital, New Delhi, India.

Dandy-Walker syndrome (DWS) is a rare congenital cystic malformation of the posterior cranial fossa. Patients show signs and symptoms of complex clinical manifestations, ranging from cranial nerve and cerebellar dysfunctions to extracranial abnormalities, which may pose challenges in dental management. This article represents a rare case of a 12-year-old girl with DWS along with the involvement of the oral cavity.
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http://dx.doi.org/10.4103/JISPPD.JISPPD_343_18DOI Listing
March 2020

Evaluation of oral health of 6 to 10-year-old asthmatic children receiving bronchodilator through inhaler.

Indian J Dent Res 2019 Sep-Oct;30(5):670-677

Department of Pedodontics and Preventive Dentistry, University College of Medical Sciences and GTB Hospital, New Delhi, India.

Aim: The aim of this study was to evaluate the oral health status in 6 to 10-year-old asthmatic children receiving bronchodilator (salbutamol, salmeterol, etc.) through inhaler and compare them with nonasthmatic healthy children.

Settings And Design: The present study was carried out at pediatric and pedodontic department and neighboring government school. It was an observational and case-control study.

Statistical Analysis: All data were analyzed using SPSS 20.0 software program and presented as mean ± standard error of mean. Chi-square test was used for the categorical data between groups. Numerical data were analyzed by Mann-Whitney U-test and t-test. Kruskal-Wallis test was performed for comparisons of median value of decayed, missing, filled surface and Decayed, Missing, Filled Surface (dmfs and DMFS) for different variables within asthmatic group. Mann-Whitney U-test for multiple comparisons and P value was adjusted according to Bonferroni correction. Negative binomial analysis was used to calculate adjusted dmfs and DMFS, and univariate analysis of variance was used for adjusted mean plaque and gingival index.

Materials And Methods: The study group composed of 70 asthmatic and 70 nonasthmatic children with the same age and social background aged between 6 and 10 years old. Oral health status was assessed using caries, plaque, and gingival index. Dental caries examination was done using the WHO criteria (1997), plaque index by Silness and Loe in 1964 and gingival health by Loe and Silness in 1963.

Results: The children in the asthmatic group had significantly higher caries prevalence, severity of dental plaque, and gingivitis compared with the nonasthmatic group. Plaque accumulation and gingivitis increased significantly as severity and duration of asthma increased.

Conclusions: Bronchial asthma had an overall deleterious effect on caries prevalence and severity, plaque, and gingivitis on primary and permanent teeth.
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http://dx.doi.org/10.4103/ijdr.IJDR_593_14DOI Listing
December 2019

Pentalogy of Fallot: A case report and overview dental implications.

Spec Care Dentist 2020 Jan 3;40(1):121-126. Epub 2019 Dec 3.

Department of Oral and Maxillofacial Surgery, Lady Hardinge Medical College, Delhi, India.

Pentalogy of Fallot is a rare congenital cyanotic heart disease and a variant of tetralogy of Fallot, in which tetralogy of Fallot is associated additionally with an atrial septal defect. It is characterized by right to left intracardiac shunting of blood leading to decreased pulmonary blood flow resulting in the development of cyanotic episodes. The case report aims to present the dental management of an 8-year-old child with a repaired cardiac anomaly of pentalogy of Fallot. His medical condition was assessed and physician consent was sought for procedural intervention. All invasive procedures were planned under antibiotic prophylaxis to prevent bacteremia associated endocarditis. Elaborate chairside dental intervention was carried out beginning with preventive schedule, oral prophylaxis and topical fluoride application followed by interception of carious progression with multiple GIC restorations and extractions of retained and grossly decayed teeth. Patient was reviewed on follow-up visit and no pain, discomfort, or complications were reported. Based on the case report it can be concluded that the medical status in patients affected with Pentalogy of Fallot must be taken into consideration to plan dental treatment and precautions must be taken for prevention of stress induced cyanosis and bacterial endocarditis in such cases.
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http://dx.doi.org/10.1111/scd.12433DOI Listing
January 2020

Clinical Pharmacokinetics and Pharmacodynamics of Risankizumab in Psoriasis Patients.

Clin Pharmacokinet 2020 03;59(3):311-326

Clinical Pharmacology and Pharmacometrics, AbbVie Inc, 1 North Waukegan Road, North Chicago, IL, 60064, USA.

Risankizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody developed and approved for the treatment of moderate-to-severe plaque psoriasis at a dose of 150 mg administered subcutaneously at weeks 0 and 4, and every 12 weeks thereafter. Ongoing trials are investigating the use of risankizumab in other inflammatory autoimmune diseases. Risankizumab exhibits linear pharmacokinetics when administered intravenously (0.01 mg/kg-1200 mg) or subcutaneously (0.25 mg/kg-300 mg), with a long terminal half-life of approximately 28 days. Following subcutaneous administration, peak plasma concentration was reached approximately 3-14 days after dosing, with an estimated bioavailability of 89%. Population pharmacokinetic analyses identified bodyweight, high titers of antidrug antibodies occurring in < 2% of evaluated subjects, baseline serum albumin, baseline high-sensitivity C-reactive protein, and baseline serum creatinine to be statistically correlated with risankizumab clearance, but none of them had a clinically meaningful impact on risankizumab efficacy in psoriasis patients following the clinical dosing regimen. Exposure-response analyses in psoriasis patients demonstrated that the maximum efficacy was achieved with the clinically approved regimen and there was no apparent correlation between risankizumab exposure and safety. A dedicated drug interaction cocktail study in patients with psoriasis demonstrated a lack of therapeutic protein-drug interaction potentials for risankizumab and various cytochrome P450 substrates. In this article, we review the clinical pharmacology data available to date for risankizumab, which supported the clinical development program and ultimately regulatory approvals for risankizumab in the treatment of patients with moderate-to-severe plaque psoriasis.
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http://dx.doi.org/10.1007/s40262-019-00842-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051925PMC
March 2020

Exposure-Response Relationships for the Efficacy and Safety of Risankizumab in Japanese Subjects with Psoriasis.

Clin Pharmacokinet 2020 05;59(5):575-589

Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.

Background And Objective: Risankizumab, a humanized monoclonal interleukin-23 antagonist antibody, has efficacy for treatment of plaque psoriasis, generalized pustular psoriasis (GPP) and erythrodermic psoriasis (EP). These analyses characterized the relationships between risankizumab exposures and key efficacy and safety variables in Japanese patients with moderate-to-severe plaque psoriasis, GPP, or EP following treatment with 75 or 150 mg subcutaneous doses at weeks 0, 4, and every 12 weeks thereafter.

Methods: Risankizumab average plasma concentrations (Cavg) were correlated with probabilities of achieving efficacy end points (PASI 75, PASI 90, PASI 100, and sPGA 0/1) using data from Japanese patients (N = 225) and non-Japanese patients (N = 1678) with moderate-to-severe plaque psoriasis enrolled in global trials, or a Japan Phase 2/3 trial.

Results: The exposure-efficacy relationships in Japanese patients were consistent with relationships for patients in global Phase 3 trials. At Week 16, a plateau of efficacy was demonstrated for 150 mg subcutaneous dose providing estimated PASI 90 and sPGA 0/1 response probabilities of 77%, and 88%, respectively. The exposures for 75 mg dose appeared to be suboptimal for PASI 100 response and other efficacy responses in heavier patients. Exposure-safety analyses (N = 242) indicated no apparent relationship between risankizumab Cavg and key safety variables, including any adverse event, serious adverse event, infection and infestation, and serious infection during treatment, consistent with observations in the global trials.

Conclusions: Overall, risankizumab 150 mg maximized efficacy, including PASI 100 response, in Japanese patients with psoriasis with no apparent relationship between exposure and evaluated safety variables.

Clinical Trial Registration: NCT03000075, NCT03022045, NCT02672852, NCT02684357, NCT02684370, NCT02694523, NCT02054481.
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http://dx.doi.org/10.1007/s40262-019-00829-2DOI Listing
May 2020

A simplified approach of prosthetic management of posttraumatic nasal obstruction using a custom-made unilateral intranasal stent in 14-year-old child.

J Indian Soc Pedod Prev Dent 2019 Jul-Sep;37(3):311-313

Department of Pedodontics and Preventive Dentistry, University College of Medical Sciences and Guru Teg Bahadur Hospital, New Delhi, India.

Infections, trauma, iatrogenic causes, congenital malformations, or complications of systemic diseases can result in perforation of the nasal septum. An intranasal stent is a removable prosthesis that can be inserted into the nasal cavity to support the form of nose. The stenting can be used for recanalization and nasal valve preservation. This case report presents a method for the fabrication of a customized nasal stent in a 14-year-old female patient with posttraumatic unilateral collapsed nasal vestibule.
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http://dx.doi.org/10.4103/JISPPD.JISPPD_232_18DOI Listing
November 2019

Meta-Analyses of Clinical Efficacy of Risankizumab and Adalimumab in Chronic Plaque Psoriasis: Supporting Evidence of Risankizumab Superiority.

Clin Pharmacol Ther 2020 02 8;107(2):435-442. Epub 2019 Nov 8.

Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, Illinois, USA.

Risankizumab, an anti-interleukin-23 monoclonal antibody, achieved significantly (P < 0.001) greater Psoriasis Area and Severity Index (PASI) and static Physician Global Assessment (sPGA) clear or almost clear (0/1) responses than adalimumab in a phase III trial in patients with moderate-to-severe psoriasis. Meta-analyses of the PASI 50, PASI 75, PASI 90, PASI 100, and sPGA0/1 responses after 16 weeks of treatment from eight (three for risankizumab and five for adalimumab) randomized, placebo-controlled trials were conducted to estimate the efficacy difference between risankizumab and adalimumab. For PASI 75, PASI 90, PASI 100, and sPGA0/1 responses, the estimated effect differences (95% confidence interval) between risankizumab and adalimumab were 15.2% (10.1%, 20.4%), 23.7% (15.7%, 31.2%), 20.8% (13.0%, 28.7%), and 20.1% (13.7%, 26.1%), respectively. These results were consistent with the observed efficacy difference from the head-to-head phase III trial, which was not included in the meta-analyses, providing independent, confirmatory evidence of the superior efficacy of risankizumab compared with adalimumab for treatment of moderate-to-severe psoriasis.
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http://dx.doi.org/10.1002/cpt.1624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006886PMC
February 2020

Exposure-Response Relationships for Efficacy and Safety of Risankizumab in Phase II and III Trials in Psoriasis Patients.

Clin Pharmacol Ther 2020 02 26;107(2):378-387. Epub 2019 Sep 26.

Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, Illinois, USA.

Risankizumab has demonstrated efficacy in phase III trials in patients with moderate-to-severe plaque psoriasis. The exposure-response relationships for risankizumab efficacy (Psoriasis Area and Severity Index (PASI)75, PASI90, PASI100, and static Physician's Global Assessment (sPGA)0/1) at week 16 (N = 1,732) and week 52 (N = 598) as well as safety (incidence of any adverse event, serious adverse event, infection and infestation, or serious infection) over up to 52 weeks were characterized using the data from risankizumab phase II and III clinical trials in patients with moderate-to-severe plaque psoriasis. Impact of clinically relevant covariates was evaluated. Risankizumab phase III regimen (150 mg subcutaneously at weeks 0, 4, and every 12 weeks thereafter) achieved the plateau of the exposure-efficacy relationships with model-estimated PASI90 and sPGA0/1 response probabilities of 77%, and 87%, respectively, at week 16 and 85%, and 88%, respectively, at week 52. There was no apparent relationship between risankizumab plasma exposure and the evaluated safety variables.
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http://dx.doi.org/10.1002/cpt.1594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006881PMC
February 2020

Pharmacokinetics of Risankizumab in Asian Healthy Subjects and Patients With Moderate to Severe Plaque Psoriasis, Generalized Pustular Psoriasis, and Erythrodermic Psoriasis.

J Clin Pharmacol 2019 12 30;59(12):1656-1668. Epub 2019 Jun 30.

Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA.

Risankizumab, a humanized monoclonal antibody that targets interleukin-23 p19 subunit, was developed for the treatment of psoriasis. This work characterizes risankizumab pharmacokinetics in Japanese and Chinese healthy subjects compared with white healthy subjects and in Japanese patients with moderate to severe plaque psoriasis, generalized pustular psoriasis, or erythrodermic psoriasis. A phase 1, single-dose study evaluated risankizumab pharmacokinetics and safety/tolerability in healthy white (18 and 300 mg subcutaneous [SC]), Japanese (18, 90, and 300 mg SC and 200, 600, and 1200 mg intravenous [IV]), and Chinese (18, 90, and 300 mg SC) subjects; pharmacokinetic data were analyzed using noncompartmental methods. Risankizumab pharmacokinetic data from phase 2/3 studies in Japanese patients with plaque psoriasis, generalized pustular psoriasis, or erythrodermic psoriasis following multiple SC doses of 75 mg or 150 mg were analyzed using a population pharmacokinetic approach along with data from the phase 1 and global phase 1 to 3 studies. Risankizumab plasma exposures (peak plasma concentration and area under the concentration-time curve) were approximately dose-proportional across 18- to 300-mg SC or 200- to 1200-mg IV doses. Risankizumab terminal elimination half-life (harmonic mean 27-34 days) was comparable across doses and ethnicities. Risankizumab exposures were approximately 20% to 30% higher in Japanese and Chinese healthy subjects compared with white healthy subjects or in Japanese patients compared with non-Japanese patients. After accounting for body-weight differences, risankizumab exposures were comparable across ethnicities. Overall, there was no ethnic impact on risankizumab pharmacokinetics, and the small difference in exposure due to body weight has no clinical relevance.
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http://dx.doi.org/10.1002/jcph.1473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852105PMC
December 2019

Pain perception and efficacy of local analgesia using 2% lignocaine, buffered lignocaine, and 4% articaine in pediatric dental procedures.

J Dent Anesth Pain Med 2019 Apr 30;19(2):101-109. Epub 2019 Apr 30.

Department of Pedodontics and Preventive Dentistry, UCMS (University of Delhi) & GTB Hospital, Delhi, India.

Background: The purpose of this study was to compare the pain perception and anesthetic efficacy of 2% lignocaine with 1:200,000 epinephrine, buffered lignocaine, and 4% articaine with 1:200,000 epinephrine for the inferior alveolar nerve block.

Methods: This was a double-blind crossover study involving 48 children aged 5-10 years, who received three inferior alveolar nerve block injections in three appointments scheduled one week apart from the next. Pain on injection was assessed using the Wong-Baker Faces pain scale and the sound eye motor scale (SEM). Efficacy of anesthesia was assessed by subjective (tingling or numbness of the lip, tongue, and corner of mouth) and objective signs (pain on probing).

Results: Pain perception on injection assessed with Wong-Baker scale was significantly different between buffered lignocaine and lignocaine (P < 0.001) and between buffered lignocaine and articaine (P = 0.041). The onset of anesthesia was lowest for buffered lignocaine, with a statistically significant difference between buffered lignocaine and lignocaine (P < 0.001). Moreover, the efficacy of local analgesia assessed using objective signs was significantly different between buffered lignocaine and lignocaine (P < 0.001) and between lignocaine and articaine.

Conclusion: Buffered lignocaine was the least painful and the most efficacious anesthetic agent during the inferior alveolar nerve block injection in 5-10-year-old patients.
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http://dx.doi.org/10.17245/jdapm.2019.19.2.101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6502762PMC
April 2019

Population Pharmacokinetics of Risankizumab in Healthy Volunteers and Subjects with Moderate to Severe Plaque Psoriasis: Integrated Analyses of Phase I-III Clinical Trials.

Clin Pharmacokinet 2019 10;58(10):1309-1321

Clinical Pharmacology and Pharmacometrics, AbbVie Inc, 1 North Waukegan Road, North Chicago, IL, 60064, USA.

Background And Objective: Risankizumab is an anti-interleukin (IL)-23 monoclonal antibody being developed for treatment of moderate to severe plaque psoriasis. This study provided a comprehensive analysis of risankizumab pharmacokinetics in healthy subjects and patients with plaque psoriasis using data across phase I-III clinical trials.

Methods: Plasma pharmacokinetic data from 1899 subjects, including 13,123 observations, who received single or multiple intravenous or subcutaneous doses of risankizumab (0.01-5 mg/kg intravenous [IV], 200-1200 mg IV, 0.25-1 mg/kg subcutaneous [SC], and 18-300 mg SC) across the phase I-III clinical program were analyzed using a non-linear mixed-effects modeling approach. The developed model was qualified and the clinical relevance of covariates statistically correlated with risankizumab clearance (CL) was evaluated using simulation analyses.

Results: Risankizumab pharmacokinetics were best described using a two-compartment model with first-order absorption and elimination. Risankizumab CL, volume of distribution at steady state (V), and terminal-phase elimination half-life (t) were estimated to be approximately 0.31 L/day, 11.2 L, and 28 days, respectively, for a typical 90 kg psoriatic subject, approaching steady-state plasma exposures by week 16 of dosing. Absolute SC bioavailability (F) was 89%. Bodyweight, anti-drug antibody (ADA) titers ≥ 128 (detected in only 1% of ADA-evaluable subjects in phase III studies), baseline serum albumin, high-sensitivity C-reactive protein (hs-CRP), and serum creatinine were statistically correlated with risankizumab CL; however, they had no clinically relevant impact on exposure.

Conclusion: Risankizumab is characterized by dose-proportional, bi-exponential disposition with no difference in exposure between healthy subjects and patients with psoriasis. None of the covariates identified as being statistically correlated with risankizumab CL has a clinically meaningful impact on its exposure with the proposed psoriasis clinical regimen of 150 mg administered SC at weeks 0 and 4, and every 12 weeks thereafter. CLINICALTRIALS.

Gov Identifiers: NCT01577550, NCT02054481, NCT02596217, NCT02684370, NCT02672852, NCT02684357, NCT02694523.
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http://dx.doi.org/10.1007/s40262-019-00759-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769095PMC
October 2019

Neonatal molar in a child with Langerhan cell histiocytosis.

J Indian Soc Pedod Prev Dent 2019 Jan-Mar;37(1):107-109

Department of Pedodontics and Preventive Dentistry, UCMS and GTB Hospital, New Delhi, India.

Teeth which erupt in the 1 month of postnatal life are known as "neonatal tooth." The incidence of these teeth ranges from 1:2000 to 1:3500 live births. Natal teeth are more common in mandibular central incisor region, followed by maxillary incisor region and mandibular canine region. The neonatal or natal teeth in the maxillary molar region are a rare occurrence. This article represents a rare case of the neonatal tooth with Langerhans cell histiocytosis.
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http://dx.doi.org/10.4103/JISPPD.JISPPD_194_18DOI Listing
July 2019

Double Lip-An Atypical Facial Anomaly: Two Case Reports.

Int J Clin Pediatr Dent 2018 Sep-Oct;11(5):451-455. Epub 2018 Oct 1.

Postgraduate Student, Department of Pedodontics, University College of Medical Sciences and Guru Teg Bahadur Hospital, New Delhi, India.

Double lip is a rare abnormality. It affects the lips, more often the upper lips and could be acquired or congenital. It may be associated with Ascher's syndrome or occur in isolation. In this deformity, there is an accessory fold of redundant mucous membrane inside the vermillion border. This cupid's bow-shaped accessory tissue is usually conspicuous during smiling but maybe occasionally visible even at rest. For the patient, this atypical facial deformity most importantly creates an aesthetic problem. Nonetheless, it may also interfere with their speech or function. Surgical excision is the treatment of choice and gives appropriate esthetic and functional results. In this article, we have presented two case reports of congenital maxillary double lip. The etiology, clinical presentation, histopathology and treatment of this infrequent anomaly have been discussed. Kalra N, Tyagi R, Khatri A, Poswal A, Panwar G, Garg K. Double Lip-An Atypical Facial Anomaly: Two Case Reports. Int J Clin Pediatr Dent. 2018;11(5):451-455.
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http://dx.doi.org/10.5005/jp-journals-10005-1556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379532PMC
October 2018

Lack of Effect of 12-Week Treatment with Risankizumab on the Pharmacokinetics of Cytochrome P450 Probe Substrates in Patients with Moderate to Severe Chronic Plaque Psoriasis.

Clin Pharmacokinet 2019 06;58(6):805-814

Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.

Objective: The objective of this study was to characterize the effects of risankizumab on the in vivo activity of cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A in psoriasis patients using a cocktail approach.

Methods: Patients with moderate to severe chronic plaque psoriasis (n = 21) received single oral doses of sensitive probe substrates for CYP1A2 (caffeine 100 mg), CYP2C9 (warfarin 10 mg), CYP2C19 (omeprazole 20 mg), CYP2D6 (metoprolol 50 mg), and CYP3A (midazolam 2 mg) on day 1, followed by 12 weeks of subcutaneous risankizumab treatment of 150 mg once every 4 weeks from day 8 to day 92, and again the same cocktail of substrates on day 98. Serial blood samples were collected for determination of the CYP probe drugs and metabolites with and without risankizumab. Trough samples were collected for risankizumab.

Results: The 90% confidence intervals (CIs) for the area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC) ratios for the CYP probe substrates administered with risankizumab versus without risankizumab were within the default 0.8-1.25 equivalence bounds. Similar results were observed for maximum plasma concentration (C), except for omeprazole, for which the lower bound of the 90% CI for C (0.73) extended slightly below the default equivalence limit. No differences were observed in metabolite-to-parent drug C or AUC ratios with risankizumab versus without risankizumab. Risankizumab trough plasma concentrations significantly exceeded those of the phase III regimen of risankizumab in psoriasis (150 mg subcutaneously at weeks 0 and 4 and every 12 weeks thereafter).

Conclusions: Risankizumab did not affect the in vivo activity of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A enzymes in patients with moderate or severe plaque psoriasis and therefore has no potential for drug interactions through these enzymes.

Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02772601.
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http://dx.doi.org/10.1007/s40262-018-0730-xDOI Listing
June 2019

Exposure-response analyses demonstrate no evidence of interleukin 17A contribution to efficacy of ABT-122 in rheumatoid or psoriatic arthritis.

Rheumatology (Oxford) 2019 02;58(2):352-360

Department of Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA.

Objectives: ABT-122 is a dual-variable-domain immunoglobulin that neutralizes both TNF-α and IL-17A. The objective of this work was to characterize exposure-response relationships for ABT-122 relative to adalimumab (TNF-α inhibitor) using ABT-122 phase 2 trials in patients with RA or PsA.

Methods: Patients received subcutaneous doses of ABT-122 ranging from 60 mg every other week (EOW) to 240 mg every week, adalimumab 40 mg EOW, or placebo (PsA patients only) for 12 weeks. Relationships between ABT-122 or adalimumab serum concentrations and time course of ACR20, ACR50 and ACR70 and PASI50, PASI75 and PASI90 responses were characterized using a non-linear mixed-effects Markov modelling approach.

Results: A total of 221 RA patients and 240 PsA patients were included in the analyses. At comparable molar exposures, there was no differentiation of efficacy between ABT-122 and adalimumab and there were no consistent differences between ABT-122 and adalimumab in the potency estimates for different efficacy endpoints based on the Markov models. Plateau of ABT-122 efficacy was achieved at exposures associated with the 120 mg EOW dose in patients with RA, which were comparable to molar exposures of adalimumab 40 mg EOW, and at the lowest dose of 120 mg every week in patients with PsA.

Conclusion: The exposure-response relationships for ABT-122 were not distinguishably different from those of adalimumab in patients with RA or PsA. Overall, there was no clear evidence that inhibition of the IL-17 pathway provided incremental benefit in the presence of TNF-α inhibition.

Trial Registration: ClinicalTrials.gov, NCT02433340, NCT02349451.
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http://dx.doi.org/10.1093/rheumatology/key312DOI Listing
February 2019

Effects of chronic kidney disease stage 4, end-stage renal disease, or dialysis on the plasma concentrations of ombitasvir, paritaprevir, ritonavir, and dasabuvir in patients with chronic HCV infection: pharmacokinetic analysis of the phase 3 RUBY-I and RUBY-II trials.

Eur J Clin Pharmacol 2019 Feb 5;75(2):207-216. Epub 2018 Oct 5.

Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.

Purpose: To characterize the pharmacokinetics of ombitasvir, paritaprevir, ritonavir, dasabuvir, and ribavirin in hepatitis C virus (HCV)-infected patients with chronic kidney disease stage 4 (CKD4) or end-stage renal disease (ESRD), including those on dialysis, in the open-label phase 3 RUBY-I and RUBY-II studies.

Methods: Patients (n = 18 CKD4, n = 68 ESRD) received ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily ± dasabuvir 250 mg twice daily ± ribavirin 200 mg once daily for 12 or 24 weeks. Intensive pharmacokinetic samples were collected from ten patients; sparse samples were collected from all patients. Arterial and venous samples were collected from three patients during hemodialysis. Area under the plasma concentration-time curve (AUC) was estimated using noncompartmental analyses for intensive data, and steady-state trough concentrations (C) were obtained from the sparse data. Pharmacokinetic results from RUBY-I and RUBY-II were compared empirically to historical data.

Results: The AUC values of ombitasvir, paritaprevir, ritonavir, and dasabuvir were comparable between CKD4 and ESRD patients and were within the range of values observed in historical studies; dialysis had no effect on drug exposures. Ribavirin was extracted during hemodialysis but had similar exposures on dialysis and non-dialysis days. Individual steady-state C values for each drug overlapped between CKD4 and ESRD patients, and values in both groups were similar to historical values.

Conclusion: Plasma concentrations of ombitasvir, paritaprevir, ritonavir, and dasabuvir were not altered by renal impairment or dialysis, suggesting these agents can be administered to HCV-infected CKD4 or ESRD patients, including those on dialysis, without dose adjustment.

Trial Registration: Clinicaltrials.gov identifiers: NCT02207088 (RUBY-I) and NCT02487199 (RUBY-II).
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http://dx.doi.org/10.1007/s00228-018-2566-6DOI Listing
February 2019

Control of Anxiety in Pediatric Patients using "Tell Show Do" Method and Audiovisual Distraction.

J Contemp Dent Pract 2018 Sep 1;19(9):1058-1064. Epub 2018 Sep 1.

Department of Pedodontics and Preventive Dentistry, M. A. Rangoonwala College of Dental Sciences & Research Centre Pune, Maharashtra, India.

Introduction: Visiting a dentist can easily evoke strong fear reactions and acute anxiety in children. It is one of the most basic reasons for avoidance and neglect of dental care. It may obstruct delivery of dental care, as the child may be unwilling to accept the treatment being provided by the dentist.

Aim: To evaluate and compare reduction in anxiety level in patients undergoing dental treatment at first dental visit.

Technique: The study was conducted on 400 patients coming to the Department of Pedodontics and Preventive Dentistry, Guru Teg Bahadur Hospital, University College of Medical Sciences, New Delhi, for their first dental visit. Anxiety was recorded using facial image scale (FIS), Venham's picture test (VPT), blood pressure, pulse rate (PR), and oxygen saturation (SpO) at different stages of the visit. Patients coming for the first dental visit were subjected to restorative treatment under Tell show do (TSD) method and audiovisual distraction (AVD). The data collected were tabulated and subjected to statistical analysis.

Conclusion: The AVD was found to be more capable in reducing anxiety than TSD. Combination of TSD and AVD had an additive effect in reduction of anxiety level and it proved to be more beneficiary.

Clinical Significance: If a child's behavior in the dental office cannot be managed, then it is difficult to hold out any dental treatment that is needed. Bringing positivity in the child's behavior would not only increase efficiency of work but would also make the experience for child undergoing treatment more pleasant.
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September 2018

Pharmacokinetics, Safety, and Tolerability of the Dual Inhibitor of Tumor Necrosis Factor-α and Interleukin 17A, ABBV-257, in Healthy Volunteers and Patients With Rheumatoid Arthritis.

Clin Pharmacol Drug Dev 2019 05 29;8(4):492-502. Epub 2018 Aug 29.

AbbVie Inc., North Chicago, IL, USA.

The dual-variable domain immunoglobulin ABBV-257 binds tumor necrosis factor-α and interleukin 17A. Following single ascending doses ( 0.3, 1.0, and 3.0 mg/kg intravenously; 0.3 and 3.0 mg/kg subcutaneously) in a randomized, double-blind, placebo-controlled study in healthy subjects (n = 40; n = 29 evaluated for pharmacokinetics), maximum observed serum concentration (C ) increased dose-proportionally, whereas area under the serum concentration-versus-time curve trended to more than dose-proportional increase. Absolute subcutaneous bioavailability was ∼80%, and the time to C (t ) occurred 6 to 8 days after subcutaneous administration. The terminal-phase harmonic mean elimination half-life (t ) ranged from 5.5 to 11 days following intravenous and subcutaneous administration. In another randomized, placebo-controlled study, rheumatoid arthritis (RA) patients (n = 8) received ABBV-257 30 mg/kg subcutaneously every other week for 8 weeks. Following the fourth dose, C was 7.69 μg/mL, and t occurred ∼4 days after dosing; t was ∼16 days. Most individuals (single-dose study, 97%; multiple-dose study, 83%) developed antidrug antibodies (ADAs). Generally, subjects with higher ADA titers had shorter ABBV-257 t and lower exposure. One serious adverse event (cerebral ischemia, considered unrelated to treatment, resolved with interventions) occurred in an RA patient who received ABBV-257. Because of the high incidence of ADA-mediated drug clearance, ABBV-257 is no longer being developed.
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http://dx.doi.org/10.1002/cpdd.611DOI Listing
May 2019

Population Pharmacokinetics of the Interleukin-23 Inhibitor Risankizumab in Subjects with Psoriasis and Crohn's Disease: Analyses of Phase I and II Trials.

Clin Pharmacokinet 2019 03;58(3):375-387

Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.

Background And Objectives: Risankizumab is a humanized anti-interleukin-23 monoclonal antibody in development for the treatment of several inflammatory diseases. This work characterized the pharmacokinetics of risankizumab and evaluated covariates that may affect its exposures using phase I and II trial data in subjects with psoriasis and Crohn's disease.

Methods: Plasma concentration measurements from a phase I study and a phase II study in subjects with psoriasis (n = 157; single doses of 0.01-5 mg/kg intravenously, 0.25-1 mg/kg subcutaneously, and 18 mg subcutaneously, and multiple doses of 90 and 180 mg subcutaneously), and a phase II study in subjects with Crohn's disease (n = 115; doses of 200 or 600 mg intravenously every 4 weeks followed by 180 mg subcutaneously every 8 weeks) were analyzed using non-linear mixed-effects modeling. The model was qualified using bootstrap and simulation-based diagnostics.

Results: A two-compartment model with first-order absorption and elimination described the pharmacokinetics of risankizumab. Considering the body weight and baseline albumin central tendency differences between disease populations, risankizumab clearance, steady-state volume of distribution, and terminal-phase elimination half-life were estimated to be approximately 0.35 L/day, 11.7 L, and 27 days, respectively, for a typical 90-kg subject with psoriasis with an albumin level of 42 g/L, and 0.31 L/day, 8.45 L, and 22 days, respectively, for a typical 65-kg subject with Crohn's disease with an albumin level of 37 g/L. Risankizumab absolute subcutaneous bioavailability and absorption rate constant were 72% and 0.18 day, respectively. Inter-individual variability for clearance was 37%.

Conclusions: Risankizumab displayed pharmacokinetic characteristics typical for an IgG1 monoclonal antibody with no apparent target-mediated disposition. Accounting for the effects of body weight and baseline albumin explained the small differences in the pharmacokinetics of risankizumab between psoriasis and Crohn's disease, with no further differences between the patient populations.
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http://dx.doi.org/10.1007/s40262-018-0704-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373392PMC
March 2019

Dual inhibition of tumour necrosis factor and interleukin-17A with ABT-122: open-label long-term extension studies in rheumatoid arthritis or psoriatic arthritis.

Rheumatology (Oxford) 2018 11;57(11):1972-1981

Rheumatology and Rehabilitation, Poznan University of Medical Sciences, Poznan, Poland.

Objectives: To evaluate the safety and maintenance of efficacy with ABT-122, a bi-specific monoclonal antibody targeting TNF and IL-17A, in patients with RA or PsA in open-label, 24-week extensions [open-label extensions (OLEs)] of 12-week, randomized, double-blind studies.

Methods: All patients received ABT-122 (RA, 120 mg; PsA, 240 mg) subcutaneously every other week on background MTX. Safety assessments included adverse events (AEs) and laboratory parameters. Efficacy was evaluated with ACR responses, 28-joint DAS using high-sensitivity CRP [DAS28 (hsCRP)], and Psoriasis Area and Severity Index (PsA study).

Results: The RA OLE study enrolled 158 patients; the PsA OLE study enrolled 168 patients. In the RA OLE study, the incidence of treatment emergent AEs (TEAEs; 41%) appeared similar to the double-blind study (36-43%). In the PsA OLE study, 57% of patients reported ⩾1 TEAE (double-blind study, 42-53%). Most TEAEs were mild or moderate in severity. There were no neutrophil abnormalities greater than grade 2. Grade 3 and/or 4 laboratory abnormalities were reported for lymphocytes, alanine aminotransferase, aspartate aminotransferase, bilirubin and haemoglobin; the number of these severe laboratory values was low (0.6-3.0%), except grade 3 lymphocyte count decreased (11.5%) in the RA study. In both OLE studies, efficacy assessed by ACR responses and other disease activity scores was maintained over the 24 weeks.

Conclusion: ABT-122 demonstrated acceptable tolerability and maintenance of efficacy for up to 36 weeks in patients with RA or PsA receiving background MTX.

Trial Registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT02433340 and NCT02429895.
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http://dx.doi.org/10.1093/rheumatology/key173DOI Listing
November 2018

Phase II Study of ABT-122, a Tumor Necrosis Factor- and Interleukin-17A-Targeted Dual Variable Domain Immunoglobulin, in Patients With Psoriatic Arthritis With an Inadequate Response to Methotrexate.

Arthritis Rheumatol 2018 11;70(11):1778-1789

AbbVie Inc., North Chicago, Illinois.

Objective: To investigate the safety and efficacy of ABT-122, a tumor necrosis factor (TNF)- and interleukin-17A (IL-17A)-targeted dual variable domain immunoglobulin, in patients with active psoriatic arthritis (PsA) who have experienced an inadequate response to methotrexate.

Methods: Patients (n = 240) were randomized to receive ABT-122 (120 or 240 mg every week), adalimumab (40 mg every other week), or placebo in a 12-week double-blind, parallel-group study. The primary efficacy end point was the proportion of patients achieving ≥20% improvement in disease activity according to the American College of Rheumatology response criteria (ACR20) at week 12. Secondary and exploratory 12-week end points included 50% improvement (ACR50) and 70% improvement (ACR70) response rates, and proportion of patients meeting the Psoriasis Area and Severity Index (PASI) response criteria for ≥75% (PASI75) and ≥90% (PASI90) improvement in skin scores among those with ≥3% of their body surface area affected by psoriasis.

Results: In both ABT-122 dose groups, ACR20 response rates at week 12 (64.8-75.3%) were superior to that in patients receiving placebo (25.0%) (P < 0.001) but similar to that in patients receiving adalimumab (68.1%). ACR50 and ACR70 response rates were also superior in both ABT-122 dose groups (36.6-53.4% and 22.5-31.5%, respectively) compared to the placebo group (12.5% and 4.2%, respectively) (P < 0.05). Among eligible patients in the placebo, adalimumab, ABT-122 120 mg every week, and ABT-122 240 mg every week treatment groups, PASI75 responses were achieved in 27.3%, 57.6%, 74.4%, and 77.6% of patients, respectively, whereas PASI90 responses were achieved in 18.2%, 45.5%, 48.8%, and 46.9% of patients, respectively. Frequencies of treatment-emergent adverse events, including infections, were similar across all treatment groups, causing no discontinuations. No serious infections or systemic hypersensitivity reactions were reported with ABT-122.

Conclusion: Dual neutralization of TNF and IL-17A with ABT-122 had efficacy and safety that was similar to, and not broadly differentiated from, that of adalimumab over a 12-week treatment course in patients with PsA.
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http://dx.doi.org/10.1002/art.40579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221045PMC
November 2018

ABT-122, a Bispecific Dual Variable Domain Immunoglobulin Targeting Tumor Necrosis Factor and Interleukin-17A, in Patients With Rheumatoid Arthritis With an Inadequate Response to Methotrexate: A Randomized, Double-Blind Study.

Arthritis Rheumatol 2018 11 10;70(11):1710-1720. Epub 2018 Oct 10.

AbbVie Incorporated, North Chicago, Illinois.

Objective: Tumor necrosis factor (TNF) and interleukin-17A (IL-17A) may independently contribute to the pathophysiology of rheumatoid arthritis (RA). This study sought to evaluate the safety and efficacy of ABT-122, a novel dual variable domain immunoglobulin targeting human TNF and IL-17A, in patients with RA who have experienced an inadequate response to methotrexate.

Methods: Patients with active RA who were receiving treatment with methotrexate and had no prior exposure to biologic agents (n = 222) were enrolled in a 12-week phase II randomized, double-blind, active-controlled, parallel-group study. Patients were randomized to receive either ABT-122 at dosages of 60 mg every other week, 120 mg every other week, or 120 mg every week or adalimumab at 40 mg every other week, administered subcutaneously. The primary efficacy end point was the proportion of patients achieving a ≥20% improvement response based on the American College of Rheumatology criteria for 20% improvement (ACR20) at week 12.

Results: Treatment-emergent adverse events were similar across all treatment groups, with no serious infections or systemic hypersensitivity reactions reported with ABT-122. ACR20 response rates at week 12 were 62%, 75%, and 80% with ABT-122 60 mg every other week, 120 mg every other week, and 120 mg every week, respectively, compared with an ACR20 response rate of 68% with 40 mg adalimumab every other week. The corresponding response rates for ACR50 and ACR70 improvement in the ABT-122 dose groups and adalimumab group were 35%, 46%, 47%, and 48%, respectively, and 22%, 18%, 36%, and 21%, respectively.

Conclusion: Over the 12-week study period, dual inhibition of TNF and IL-17A with ABT-122 produced a safety profile consistent with that of adalimumb used for inhibition of TNF alone. The efficacy of ABT-122 over 12 weeks at dosages of 120 mg every other week or 120 mg every week was not meaningfully differentiated from that of adalimumab at a dosage of 40 mg every other week in patients with RA receiving concomitant methotrexate.
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http://dx.doi.org/10.1002/art.40580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704363PMC
November 2018

Industry Perspective on Standardizing Food-Effect Studies for New Drug Development.

Clin Pharmacokinet 2018 08;57(8):901-909

Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064-1802, USA.

Investigating the effect of food on bioavailability during the development of an oral drug product is of prime importance because it has major implications on the study design of the clinical trials and dosing and administration recommendations. For modified-release formulations that exhibit dose dumping when administered with food, this may result in clinical concerns around safety and efficacy. In this article, we provide an overview of the various considerations in our opinion that impact the design and conduct of food-effect studies. We summarize the various recommendations from the different regulatory agencies and provide specific suggestions on study conduct in terms of statistical design, timing of studies, subject selection, and type and caloric content of the meal. We also discuss the role of modeling and simulation. Finally, we present an interpretation of the results of food-effect studies in addition to dosing and labeling recommendations in relation to regulatory guidance documents.
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http://dx.doi.org/10.1007/s40262-018-0630-0DOI Listing
August 2018

Population Pharmacokinetics of the TNF-α and IL-17A Dual-Variable Domain Antibody ABT-122 in Healthy Volunteers and Subjects With Psoriatic or Rheumatoid Arthritis: Analysis of Phase 1 and 2 Clinical Trials.

J Clin Pharmacol 2018 06 24;58(6):803-813. Epub 2018 Jan 24.

Clinical Pharmacology and Pharmacometrics, AbbVie, North Chicago, IL, USA.

ABT-122 is an IgG1 dual-variable domain immunoglobulin that specifically blocks TNF-α and IL-17A. This work characterized ABT-122 pharmacokinetics using nonlinear mixed-effects modeling and ABT-122 serum concentrations from 72 healthy subjects, 196 subjects with rheumatoid arthritis (RA), and 144 subjects with psoriatic arthritis (PsA) enrolled in 4 phase 1 and 2 phase 2 studies (0.1-10 mg/kg intravenously and 0.3-3 mg/kg subcutaneous single doses and 0.3-3.0 mg/kg subcutaneous and 60-240 mg subcutaneous doses weekly or every other week). A 2-compartment model with a combination of linear clearance (0.419 L/day) and nonlinear clearance (relevant only at low doses; V and K of 0.155 mg/day and 0.0458 mg/L, respectively) described ABT-122 pharmacokinetics. Subcutaneous bioavailability was 35%-58% across formulations and populations. Body weight was a significant covariate for ABT-122 clearance, with subjects with body weight of 140 and 40 kg estimated to have 38% lower and 43% higher ABT-122 AUC, respectively, compared with a 70-kg reference subject. ABT-122 antidrug antibody (ADA) titer (ADA incidence, 47%; 0 to 519 000 titer range in the data set) was a continuous covariate on ABT-122 clearance. An ADA titer of 100 units resulted in a 5-fold increase in clearance. Sex, age, and baseline serum albumin or baseline C-reactive protein level did not impact ABT-122 exposure. Fixed-effects and random-effects parameters were estimated with a relative standard error of ≤17% and ≤28%, respectively, and the model was qualified using bootstrap analysis and visual predictive checks. This analysis characterized ABT-122 exposure across populations and supported exposure-response analyses of ABT-122 efficacy in RA and PsA.
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http://dx.doi.org/10.1002/jcph.1068DOI Listing
June 2018

Safety, Tolerability, and Pharmacodynamics of ABT-122, a Tumor Necrosis Factor- and Interleukin-17-Targeted Dual Variable Domain Immunoglobulin, in Patients With Rheumatoid Arthritis.

Arthritis Rheumatol 2017 12 8;69(12):2283-2291. Epub 2017 Nov 8.

AbbVie, North Chicago, Illinois.

Objective: Tumor necrosis factor (TNF) and interleukin-17 (IL-17) independently contribute to the pathophysiology of rheumatoid arthritis (RA). ABT-122 is a novel dual variable domain immunoglobulin that selectively and simultaneously targets human TNF and IL-17A. The aim of treatment with ABT-122 is to evoke a greater clinical response than that achieved by targeting either cytokine alone. This study was undertaken to present the pooled safety, tolerability, and exploratory pharmacodynamics of ABT-122 based on 2 phase I, placebo-controlled, multiple ascending-dose studies in patients with primarily inactive RA.

Methods: Patients (n = 44) receiving stable dosages of methotrexate (2.5-25 mg/week) were randomized to receive subcutaneous placebo, ABT-122 1 mg/kg every other week (4 doses), or ABT-122 0.5, 1.5, or 3 mg/kg weekly (8 doses) and were evaluated through 45 days after the last dose (day 92). Serum samples for the assessment of inflammation markers and chemokines were collected at baseline and on postdose days 3, 5, 8, 15, 29, 57, 64, 78, and 92.

Results: No clinically significant findings regarding the safety of ABT-122 were observed. The rates of treatment-emergent adverse events (AEs) were similar in patients receiving ABT-122 and those receiving placebo. Only 1 serious AE (and no systemic hypersensitivity reactions or dose-limiting toxicities) was observed in patients treated with ABT-122. The incidence of infections was similar between patients treated with ABT-122 and those receiving placebo, with no serious infection reported. The levels of CXCL9, CXCL10, CCL23, and soluble E-selectin were significantly decreased following ABT-122 treatment relative to placebo treatment. Although patients had essentially inactive RA, exploratory clinical parameters suggested potential antiinflammatory effects following treatment with ABT-122.

Conclusion: The results of these phase I studies suggest that dual neutralization of TNF and IL-17 with ABT-122 has characteristics acceptable for further exploration of therapeutic potential in TNF- and IL-17A-driven immune-mediated inflammatory diseases.
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http://dx.doi.org/10.1002/art.40319DOI Listing
December 2017

Clinical and radiographic comparison of platelet-rich fibrin and mineral trioxide aggregate as pulpotomy agents in primary molars.

J Indian Soc Pedod Prev Dent 2017 Oct-Dec;35(4):367-373

Department of Pedodontics and Preventive Dentistry, University College of Medical Sciences, Guru Teg Bahadur Hospital, New Delhi, India.

Aim: This study aimed to evaluate and compare the Platelet-rich fibrin (PRF) and Mineral trioxide aggregate (MTA) as a pulpotomy agent in primary molars.

Material And Methods: In this study, 50 primary molars from 50 healthy children aged 5-9 years requiring pulpotomy were randomly allocated into two groups. In PRF group, after coronal pulp removal and hemostasis, remaining pulp tissue was covered with PRF preparation. In the MTA group, the pulp stumps were covered with MTA (Pro Root MTA-Root Canal Repair Material, Dentsply International Inc.) paste obtained by mixing MTA powder with sterile water at a 3:1 powder to water ratio. All teeth were restored with reinforced zinc oxide eugenol base and glass - ionomer cement. Stainless steel crowns were given in both groups 24 h after treatment. Clinical evaluation was undertaken at 1, 3, and 6 months intervals whereas radiographic evaluation of the treated teeth was carried out at the interval of 6 months.

Results: By the end of 6 months, the overall success rate was 90% in PRF group and 92% in MTA Group. A statistically significant difference was observed between the groups at 6 months of follow-up (P < 0.05). The results were statistically nonsignificant between the groups (P > 0.05).

Conclusion: Radiographic and clinical outcome in PRF group could suggest it as an acceptable alternative in pulpotomy of primary teeth. PRF holds a promising future in the area of primary tooth vital pulp therapy.
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http://dx.doi.org/10.4103/JISPPD.JISPPD_178_17DOI Listing
June 2018

An Appraisal of the Prevalence and Attributes of Traumatic Dental Injuries in the Permanent Anterior Teeth among 7-14-Year-Old School Children of North East Delhi.

Contemp Clin Dent 2017 Apr-Jun;8(2):218-224

Department of Paedodontics and Preventive Dentistry, University College of Medical Sciences, Delhi University, New Delhi, India.

Aims: The aim of this study was to assess the prevalence, associated risk factors, characteristics, and pattern of traumatic dental injuries (TDIs) in the permanent anterior teeth among school children of North East Delhi area.

Settings And Design: A cross-sectional study was done in 3000 school-going children aged 7-14 years.

Materials And Methods: A detailed case history and clinical examination were performed on the entire sample population. TDIs were recorded according to Andreasen's epidemiological classification of TDIs including World Health Organization codes.

Statistical Analysis Used: For finding the independent association of the significant variables with outcome, multivariable logistic regression analysis was used.

Results: A prevalence of 10.7% was observed in the sample being studied. Dental trauma was significantly ( < 0.05) associated with male gender, and high statistical significance ( < 0.001) was noted with age, participation in sports, lip seal, and overjet. Fall of the child while playing by himself/herself was the most common cause; afternoon and schools were the most common time and place of occurrence of TDIs, respectively. Single tooth enamel fractures in the left maxillary central incisors were most commonly seen. Adhesive restorations were the most frequent form of treatment required.

Conclusions: Organizing studies addressing the prevention and treatment needs of TDIs and educational programs aimed toward parents and school teachers are of paramount importance. Furthermore, recognizing the tremendous treatment negligence is extremely critical to adequately analyze indifference of the people toward dental trauma and its consequences.
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http://dx.doi.org/10.4103/ccd.ccd_133_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551325PMC
August 2017

Pharmacokinetics of ABT-122, a TNF-α- and IL-17A-Targeted Dual-Variable Domain Immunoglobulin, in Healthy Subjects and Patients with Rheumatoid Arthritis: Results from Three Phase I Trials.

Clin Pharmacokinet 2018 05;57(5):613-623

AbbVie Inc, 1 North Waukegan Road, North Chicago, IL, 60064, USA.

Background And Objective: ABT-122 is a dual-variable domain immunoglobulin that neutralizes both tumor necrosis factor-α and interleukin-17A, with the goal of achieving greater clinical efficacy than can be achieved by blocking either cytokine alone. This work characterized the pharmacokinetics of ABT-122 in healthy subjects and in patients with rheumatoid arthritis.

Methods: ABT-122 pharmacokinetics was evaluated in three phase I studies. In Study 1, single intravenous (0.1, 0.3, 1, 3, and 10 mg/kg) and subcutaneous (0.3, 1, and 3 mg/kg) doses were evaluated in healthy subjects. In Studies 2 and 3, multiple subcutaneous doses (1 mg/kg every other week or 0.5-3 mg/kg every week) were evaluated for 8 weeks in patients with rheumatoid arthritis on stable methotrexate therapy. Pharmacokinetic data were available from 48 healthy subjects and 31 patients with rheumatoid arthritis.

Results: ABT-122 showed multi-exponential disposition with more than dose-proportional exposures at the 0.1-1 mg/kg doses and approximately dose-proportional exposures at doses ≥1 mg/kg. ABT-122 absolute subcutaneous bioavailability was approximately 50% with maximum serum concentrations observed 3-4 days after dosing. Steady state was achieved by week 6 of subcutaneous dosing. ABT-122 maximum serum concentration-to-trough concentration ratio was 2.6 for every other week dosing and 1.3 for every week dosing, corresponding to an effective half-life of 10-18 days. ABT-122 median area under the serum concentration-time curve accumulation ratio was 3.8-4.8 with every week dosing. Measureable antidrug antibodies were observed in all 48 subjects in Study 1 by day 15 post-dose and 19 of 31 ABT-122-treated patients in Studies 2 and 3 [median time to appearance of antidrug antibodies of 64 days (range 15-92 days)]. No dose-limiting toxicities were observed in these studies and the maximum tolerated dose was not identified.

Conclusions: Results from these three phase I studies supported testing ABT-122 every week and every other week regimens in phase II trials in subjects with rheumatoid and psoriatic arthritis. Study 2 (EudraCT: 2012-003448-54); Study 3 (NCT01853033).
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http://dx.doi.org/10.1007/s40262-017-0580-yDOI Listing
May 2018

Application of Exposure-Response Analyses to Establish the Pharmacodynamic Similarity of a Once-Daily Regimen to an Approved Twice-Daily Dosing Regimen for the Treatment of HCV Infection.

AAPS J 2017 09 6;19(5):1523-1535. Epub 2017 Jul 6.

Clinical Pharmacokinetics and Pharmacodynamics, AbbVie Inc, North Chicago, Illinois, USA.

The triple direct-acting antiviral (3-DAA) regimen (two co-formulated tablets of ombitasvir/paritaprevir/ritonavir once daily and one tablet of dasabuvir twice daily) for patients with hepatitis C virus (HCV) genotype 1 infection has been reformulated for once-daily administration containing all three active DAAs (3QD regimen). Two bioequivalence studies compared the 3-DAA and 3QD regimens. In study 1, fed, single-, and multiple-dose crossover comparisons revealed exposures for drug components that were slightly outside the bioequivalence criteria, i.e., 21 to 29% lower dasabuvir C , paritaprevir C , and ritonavir C . In study 2, fed and fasted single-dose crossover comparisons demonstrated a large impact of food on exposures, confirming the product's labeling requirement for administration only with food, and revealed a lack of bioequivalence under fasting conditions. Exposure-response analyses using efficacy data from phase 2/3 studies of the 3-DAA regimen demonstrated that the lower dasabuvir C for the 3QD regimen (under fed condition) would have minimal impact on sustained virologic response at week 12 post-treatment (SVR). Thus, the pharmacodynamic similarity between the regimens was established and the analyses provided the basis for regulatory approval of the 3QD regimen to treat patients with chronic HCV genotype 1 infection.
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http://dx.doi.org/10.1208/s12248-017-0115-3DOI Listing
September 2017

Prosthetic Rehabilitation of an Insidiously Enlarged Traumatic Palatal Perforation after Orotracheal Intubation in a Young Diabetic Child.

J Clin Diagn Res 2017 Apr 1;11(4):ZD38-ZD39. Epub 2017 Apr 1.

Postgraduate Student, Department of Pedodontics and Preventive Dentistry, University College of Medical Sciences, Delhi University, Delhi, India.

This report describes an unusual case of an insidiously enlarged traumatic palatal perforation after orotracheal intubation in a four-year-old female child with Insulin Dependent Diabetes Mellitus (IDDM). The child was first diagnosed with diabetes at 10 months of age when she was hospitalized for pneumonia. Severe respiratory distress warranted assisted ventilation via orotracheal intubation. Multiple factors namely infection, relative immunodeficiency, poor wound healing, trauma via orotracheal intubation as well as uncontrolled glucose levels, all contributed to the formation and deterioration of the palatal perforation. A palatal obturator was fabricated as an interim treatment until surgical closure could be performed.
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http://dx.doi.org/10.7860/JCDR/2017/25751.9749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5449943PMC
April 2017