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Biomedical subjects

H Rubie

Publications and source records attributed to H Rubie.

At least 19 recordsLinked to original sources

HIGM syndrome caused by insertion of an AluYb8 element in exon 1 of the CD40LG gene.

A new mutation of the CD40LG gene that encodes the CD40 ligand molecule was characterized in a young patient harboring a hyper-IgM with immunodeficiency syndrome. Inactivation of CD40LG gene resulted from the insertion of an AluYb8 element in exon 1 responsible for a total deficiency of CD40 ligand expression by T lymphocytes. Maternal transmission of the X-linked mutation was confirmed by gene-specific polymerase chain reaction. This is the 17th case report concerning a human genetic disease caused by an Alu element insertion in a coding sequence.

Alu Elements↗

[Central venous totally implantable access for high dose chemotherapy in children].

BACKGROUND: The feasibility and complication rate of central venous totally implantable access ports (TIAP), used for delivering high-dose chemotherapy (HDC) with autologous stem cell transplantation, have not been fully investigated to date, due to the almost exclusive use of external catheters (EC) in this clinical setting. PATIENTS AND METHODS: We retrospectively studied infectious and mechanical complications of 45 TIAP and 19 EC, in 64 children receiving HDC and autologous stem cell transplantation at the Centre Leon-Berard (Lyon) or at the oncology unit of Toulouse children hospital between January 1999 and December 2003. RESULTS: From the beginning of intensification to 60 days after bone marrow transplantation, 7 catheter-related bloodstream infections (3/19 EC or 15.8% corresponding to 2.69 infections for 1000 days of observation; 4/45 TIAP or 8.9% corresponding to 1.38 infections for 1000 days of observation) and 2 local infections (1/45 TIAP; 1/19 EC) were reported. Seven cases of reversible obstruction (6/7 with TIAP) and no deep venous thrombosis were detected. In 7 cases, another venous access was required either for accidental removal (2 EC), catheter infection (2 TIAP), or admission to intensive care (2 TIAP, 1 EC). TIAP complication rate does not seem to be influenced by factors such as low weight, massive blood product transfusion or prolonged parenteral nutrition. In 8 children, TIAP were used for collection of hematopoietic progenitor cells. CONCLUSIONS: The use of TIAPs appears as a safe and effective option for HDC. We found more mechanical complications but less infectious complications with TIAP than with EC. Nevertheless, results need to be validated prospectively in a larger study cohort.

Adult↗

Dose finding and O6-alkylguanine-DNA alkyltransferase study of cisplatin combined with temozolomide in paediatric solid malignancies.

Cisplatin may have additive activity with temozolomide due to ablation of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (MGMT). This phase I/II study determined recommended combination doses using the Continual Reassessment Method, toxicities and antitumour activity in paediatric patients, and evaluated MGMT in peripheral blood mononuclear cells (PBMCs) in order to correlate with haematological toxicity. In total, 39 patients with refractory or recurrent solid tumours (median age approximately 13 years; 14 pretreated with high-dose chemotherapy, craniospinal irradiation, or having bone marrow involvement) were treated with cisplatin, followed the next day by oral temozolomide for 5 days every 4 weeks at dose levels 80 mg m(-2)/150 mg m(-2) day(-1), 80/200, and 100/200, respectively. A total of 38 patients receiving 113 cycles (median 2, range 1-7) were evaluable for toxicity. Dose-limiting toxicity was haematological in all but one case. Treatment-related toxicities were thrombocytopenia, neutropenia, nausea-vomiting, asthenia. Hearing loss was experienced in five patients with prior irradiation to the brain stem or posterior fossa. Partial responses were observed in two malignant glioma, one brain stem glioma, and two neuroblastoma. Median MGMT activity in PBMCs decreased after 5 days of temozolomide treatment: low MGMT activity correlated with increased severity of thrombocytopenia. Cisplatin-temozolomide combinations are well tolerated without additional toxicity to single-agent treatments; the recommended phase II dosage is 80 mg m(-2) cisplatin and 150 mg m(-2) x 5 temozolomide in heavily treated, and 200 mg m(-2) x 5 temozolomide in less-heavily pretreated children.

Adolescent↗

Long-term renal and hearing toxicity of carboplatin in infants treated for localized and unresectable neuroblastoma: results of the SFOP NBL90 study.

BACKGROUND: A secondary end point of the NBL90 protocol (Rubie H et al. Pediatr Oncol 2001;36:247-250) was the concern in this infant population for possible carboplatin-(CBDCA) induced late side effects including impaired renal and hearing functions. PROCEDURE: Glomerular filtration rate (GFR), tubular function (TF), pure tone audiometry (PTA), high-frequency, and transient evoked-otoacoustic emission were prospectively assessed in 30 children alive and disease-free 6 years after the end of the treatment. RESULTS: Median age at diagnosis and at assessment was 4.7 months and 7 years, respectively. Blood pressure was < or =97.5 centile in all children. The mean estimated GFR was 114 +/- 13 ml/min/1.73 m(2) by Schwartz formula [range 87-145]. TF assessment failed to demonstrate any impairment. 29/30 children had grade 0 ototoxicity and all transient evoked otoacoustic emission were normal. CONCLUSIONS: With a 6-year follow-up the combination of VP16 and carboplatin given at conventional doses is safe on renal and hearing functions in infants with unresectable neuroblastomas treated according to SFOP NB90.

Antineoplastic Agents↗

A nationwide study of granulosa cell tumors in pre- and postpubertal girls: missed diagnosis of endocrine manifestations worsens prognosis.

BACKGROUND: There are very few data on the natural history of ovarian granulosa cell tumors (OGCT) in children. The aim of this study was to determine whether early recognition and diagnosis of the initial endocrine signs could improve the outcome of these tumors. METHODS: In a nationwide study from 1990 to 2004, we analyzed the clinical, biological and pathologic data from 40 pre- and postpubertal girls presenting an OGCT. RESULTS: 1. Among the prepubertal girls (n = 29), 17 OGCTs were diagnosed on the basis of precocious pseudopuberty. None of the 17 girls had a peritoneal spread of the tumor (100% FIGO stage Ia). Diagnosis based on a tumoral or acute abdomen (12 cases) was associated with frequent intraperitoneal ruptures of the tumor (50%) and a risk of relapse (2 cases). Of the eight girls who had had a misdiagnosed precocious pseudopuberty, five had a pre- or perioperative tumoral rupture. 2. Among the postpubertal girls (n = 11), endocrine manifestations such as secondary amenorrhea or virilization had been underevaluated in three of them and the diagnosis was established from a tumoral abdomen. This clinical presentation was associated with frequent ruptures of the mass in the peritoneum (80%) and a higher risk of recurrence (30%). 3. A delayed diagnosis of OGCT despite previous endocrine signs (11 cases; 8 pre- and 3 postpubertal) was associated with a high risk of pre- or peri-operative peritoneal tumor spreading (70% FIGO stage Ic or IIc, p <0.05). The mean delay for diagnosis ranged from 3 to 11 months. CONCLUSION: This study highlights the critical role of early diagnosis of OGCT in pre- and postpubertal girls, particularly at the first seemingly banal signs of endocrine disorder. Peritoneal spread of the tumor may thereby be prevented, which improves the prognosis.

Abdominal Pain↗

Carboplatin-epirubicin regimen for the treatment of hepatoblastoma.

BACKGROUND: In order to lower the long-term toxicity of chemotherapy for hepatoblastoma patients, a prospective study was designed based on pre-operative chemotherapy combining carboplatin and epirubicin (CE). PROCEDURES: Patients under 16 years of age with an epithelial hepatic tumor diagnosed by ultrasound or CT scan and a high serum alpha-foetoprotein (AFP) level were eligible. Patients were treated with a pre-operative chemotherapy regimen combining carboplatin 600 mg/m(2) and epirubicin 80 mg/m(2). Tumor resectability was assessed after four courses given at 3-week intervals. After surgery, patients were given two more courses of CE. Response was assessed based on a drop in serum AFP and tumor shrinkage. RESULTS: Between July 1988 and August 1995, 27 patients with a hepatoblastoma were included. The initial PRETEXT group according to the SIOPEL classification was: group 2 (5 pts), group 3 (15 pts), group 4 (5 pts), and 2 pts were not assessed. Six patients had lung metastases. Response was partial response (PR) in 20/27 (74%) patients, disease was stable in 3 and 4 had progressive disease (PD). A complete surgical resection was performed in 21 pts. Five-year overall and disease-free survival (DFS) were respectively 56% (95%CI: 37-72%) and 63% (95%CI: 44-78%). During the same time period, 7 pts with a hepatocellular carcinoma were treated according to this protocol. Only one achieved a PR. Toxicity was mostly hematologic with > or =grade 3 leukopenia in 23% of the courses, > or =grade 3 thrombocytopenia in 29% of the courses and anemia in 22%. CONCLUSION: The CE protocol is feasible and efficient in hepatoblastoma. However, only a randomized study will permit a valid comparison of the efficacy of cisplatin and carboplatin for the treatment of these patients.

Adolescent↗

[Neonatal localized neuroblastoma: 52 cases treated from 1990 to 1999].

UNLABELLED: Neuroblastoma is the most frequent tumor observed in the newborn. The aim of this study was to review clinical features, treatment and outcome of newborns diagnosed with a localized neuroblastoma. POPULATION AND METHODS: Data from 52 cases treated according to the NBL 90 and 94 protocols between 1990 and 1999 in 18 French centers of pediatric oncology were analyzed. RESULTS: The median age at diagnosis was 12 days (range 0-28) with antenatal detection in 14 patients (27%). Tumor location was abdominal in 40 patients (adrenal in 20 of the 40), thoracic in eight, pelvic in three, and cervical in one. N-myc amplification was observed in one out of 40 evaluable cases. The size of the primary tumor was less than 5 cm in 25 cases, between 5 and 10 cm in 25 and more than 10 cm in two. Dumbbell tumor was observed in seven, of whom five had neurological deficit. One child died from hemorrhage after fine needle biopsy during diagnostic procedure. Primary surgical resection was attempted in 37 infants, of whom two died of surgery related complications and three had nephrectomy. Tumor was deemed as unresectable in 14 patients, and primary chemotherapy was given followed by surgical excision in 12. One of them died a few days after the beginning of chemotherapy. As a whole, continuous complete remission was achieved in 48 children, four of them after relapse. Overall survival was 92% with a median follow-up of 46 months (0-113 months). CONCLUSION: The excellent prognosis of localized NB in neonates needs very restrictive surgical indications, with well-established anatomic and imaging criteria. Indeed, chemotherapy based on weight and managed by expert teams should allow to perform surgical excision in safer conditions for unresectable tumors.

Antineoplastic Combined Chemotherapy Protocols↗

[Prognosis of neuroblastoma in childhood. Methods of assessment and clinical use].

Neuroblastoma and its benign counterpart, ganglioneuroma, are pediatric neuroblastic tumors arising in the sympathetic nervous system from neural-crest cells. Neuroblastoma, the most common extra-cranial solid tumour during childhood, is unique for its broad spectrum of clinical virulence from spontaneous remission to rapid and fatal progression despite intensive multimodality therapy. To a large extent, outcome could be predicted by the stage of disease and the age at diagnosis. However, a number of molecular events in neuroblastoma tumors, accounting for the variability of outcome and response to therapy, have been identified over the past decades. Among these, MYCN amplification is the most relevant prognostic factor and was the first genetic marker, in paediatric oncology, to be included in clinical strategies as a guide for therapeutic decision. This has allowed the most suitable intensity of therapy to be delivered according to a risk-stratified strategy, from observation to megadose chemotherapy with stem cell transplantation. Recent advances in understanding the biology and genetics of neuroblastoma will ultimately allow to select poor-risk patients for appropriate future biologically based therapies.

Antineoplastic Combined Chemotherapy Protocols↗

Localised and unresectable neuroblastoma in infants: excellent outcome with low-dose primary chemotherapy.

The purpose of this study was to evaluate the efficacy of low-dose chemotherapy in infants with localised and unresectable neuroblastoma (NB). All consecutive infants with localised NB and no N-myc amplification were eligible in the SFOP-NBL 94 study. Primary tumour was deemed as unresectable according to imaging data showing any risk of immediate resection. Diagnostic procedures and staging were conducted according to INSS recommendations. For children, provided that they had no threatening symptom (i.e. vital risk or dumb-bell NB with neurologic deficit), chemotherapy consisted in low-dose cyclophosphamide (5 mg(-1)kg day(-1) x 5 days) and vincristine (0.05 mg kg(-1) at day 1)-CV and repeated one to three times every 2 weeks until surgical excision can be safely performed. No postoperative treatment was given. Between January 1995 and December 1999, 134 consecutive infants with localised NB were registered in the study, of whom 39 had an unresectable NB without N-myc amplification. Among them 28 had no threatening symptom and received CV according to the protocol. Objective response was observed in 14 (50%) and the other 14 were given second-line chemotherapy because of no response. Surgery was attempted in 38 patients including 14 after CV alone, leading to complete resection in 23. Relapses occurred in four patients all local. Survival and event-free survival were 100 and 90+/-5% with a median follow-up of 55 months (range 33-93). In conclusion primary low-dose chemotherapy without anthracyclines is efficient in about half of the infants presenting with an unresectable NB and no N-myc amplification, allowing excellent survival rates without jeopardising their long-term outcome even for nonresponding patients who received standard regimen.

Antineoplastic Agents↗

Treatment of stage 4s neuroblastoma--report of 10 years' experience of the French Society of Paediatric Oncology (SFOP).

Stage 4s neuroblastoma (NB) is usually associated with a favourable outcome, despite a large tumour burden, as spontaneous regression frequently occurs. However, in some infants rapid disease progression can be observed with severe functional impairment. Thus, for all patients the potential risks of cytotoxic therapy must be weighed against the benefits of early medical intervention. We have retrospectively reviewed the charts of 94 infants treated for stage 4s NB in centres of the French Society of Paediatric Oncology between 1990 and 2000, and describe the different first-line treatment approaches that were, successively, liver irradiation, chemotherapy using a cyclophosphamide-vincristine regimen, and chemotherapy using a carboplatin-etoposide regimen. The overall survival was 88% (+/-7.6%), with a mean follow-up of 64 months. Elevated serum neuron-specific enolase (>100 nmol ml(-1)), ferritin (>280 ng ml(-1)) and urinary dopamine levels (>2500 nmol mmol(-1) creatinine) were associated with a poor outcome, as were the genetic markers N-myc amplification and chromosome 1p deletion (P<0.0005 and P=0.0016, respectively). Patients who required medical intervention at diagnosis fared worse than those who received supportive treatment only (P<0.005). The clinical evolution observed with the different successive treatment approaches suggests that if infants do require therapy, the prompt initiation of a more intensive regimen such as carboplatin-etoposide may be more beneficial.

Antineoplastic Combined Chemotherapy Protocols↗

Localized cervical neuroblastoma: prevention of surgical complications.

OBJECTIVES: The purpose of this study focused on cervical neuroblastoma (NB) was to assess the prognosis, define the most suitable methods of investigation, and evaluate risk factors for complications following primary surgery. METHODS: Between 1990 and 1999, we conducted two consecutive prospective multicentric studies (NBL90 and NBL94) on localized NB. Because the first study (1990-1994) found surgery-related morbidity and mortality, several surgical risk factors (i.e. adhesion to major vessels, size, friability, and dumb bell tumor) were defined and used prospectively as criteria of resectability in the second study (1994-1999). RESULTS: Of 617 cases included in the two studies, 43 involved cervical NB including 17 cervicothoracic tumors. With a median follow-up of 4 years, overall survival and event-free survival rates were 91 and 81%, respectively with no significant difference between cervical or cervicothoracic NB. Seventeen patients were included in the second study; surgery was used as the first line treatment in 11. Full pre-operative work-up was performed in eight patients, demonstrating one or more risk factors in three. The remaining three patients underwent emergency surgery with no pre-operative work-up or only ultrasound: two developed serious complications. All three patients presenting documented risk factors developed post-operative complications versus only two of the eight patients who presented no risk factor (n = 5) or were inadequately evaluated (n = 3) (P = 0.06). None of the five patients in whom full work-up demonstrated no risk factor had post-operative complications (P = 0.02). CONCLUSIONS: Cervical neuroblastoma has a favorable prognosis. Surgery is the treatment of choice but there is a risk of complications. Appropriate pre-operative work-up is mandatory to evaluate resectability. The surgical risk factors defined for our second study seem to be significant predictors of post-operative complications.

Female↗

Individual dosing of carboplatin based on drug monitoring in children receiving high-dose chemotherapy.

Individual dosing of carboplatin based on drug monitoring was performed within a multi-centric phase I study based on high AUC-levels in children. Twelve patients (aged 3-17 years old) have been included: 3, 5, and 4 patients at the overall target ultrafilterable carboplatin AUC of 20, 25, or 30 mg/ml x min, respectively. Carboplatin was administered as a daily 60-min infusion, repeated on five consecutive days. The initial daily dose corresponding to the three first days was calculated according to the carboplatin clearance (CL) predicted from patients' characteristics (body weight, serum creatinine and nephrectomy status). Three blood samples were taken per patient. The individual CL were estimated by MAP (maximum a posteriori approach) Bayesian method implemented in the MP-K program. The doses for day 4 and 5 was adjusted in order to obtain the overall target AUC. Drug monitoring led to a change in the carboplatin dose (overall administered dose versus overall dose planned) ranging from -41% to +45%. Pharmacokinetics were performed at day 5 for 7/12 children: mean relative change between day 1 and day 5 was -11% showing a statistically significant, but limited, decrease of CL from day 1 to day 5. The percentage of difference between the observed and target overall AUC ranged between -7% and +14%. Three patients (one at each AUC level) who were previously treated with cisplatin experienced dose-limiting hearing loss. In conclusion, drug monitoring and dose adjustment is needed for the control of carboplatin plasma exposure when administering high doses of carboplatin in children.

Adolescent↗

[Hemophagocytic syndrome associated with neutropenia after chemotherapy].

MATERIAL AND METHODS: This retrospective study reports 15 cases of hemophagocytic syndrome in children treated in our department during a eight-year period. RESULTS: Underlying diseases were acute lymphoblastic leukemia (n = 8) acute myeloblastic leukemia (n = 6) and Burkitt lymphoma (n = 1). Hemophagocytic syndrome was suspected after chemotherapy, in case of an unusual prolonged febrile neutropenia (n = 14) or isolated thrombocytopenia (n = 1). That fever was associated with cutaneous, pulmonary, hematologic, digestive and cardiac signs. Biological disorders included hypoprotidemia, hyponatremia, increased liver enzymes and fibrinopenia. Thrombocytopenia was observed in all patients and was associated with neutropenia for 14 of them. Diagnosis of hemophagocytic syndrome was always confirmed by bone marrow aspiration (infiltration with activated macrophages). Infection was documented in eight children. The treatment of hemophagocytic syndrome relied on steroids and resolution of symptoms occurred within three days of therapy. No recurrence of hemophagocytic syndrome was observed with a median follow up of two years and a half. CONCLUSION: Such complication should be suspected in cases of prolonged febrile neutropenia and/or thrombocytopenia, and confirmed by bone marrow aspiration. Indeed, steroid therapy is effective and chemotherapy can be then pursued.

Adrenal Cortex Hormones↗

[Optic pathway gliomas in neurofibromatosis type I. Longitudinal study of 30 cases in two multidisciplinary practices].

UNLABELLED: The aim of this study was to analyse the outcome of optic pathway gliomas in 30 children with neurofibromatosis type 1, the indications of treatment, and the follow-up and screening protocol. PATIENTS AND METHODS: All patients with a minimal two years follow-up (median six years, range two to 19 years), in two multidisciplinary consultations of Saint-Vincent-de-Paul (Paris) and Purpan (Toulouse) hospitals, were included in the study. In our series, we practiced systematic screening MRI in children under six years' of age or with neuropsychological deficiency that may imply an unreliable ophthalmological examination. RESULTS: Thirty-seven percent (11 patients) had progressive ophthalmological signs and were treated, and 63% (19 patients) were not progressive. Our study confirmed that most of optic pathway gliomas were stable during evolution, but rare cases may have bad prognosis. CONCLUSION: Our study supported the importance of close ophthalmological follow-up during childhood for which screening methods are discussed. There is a consensus to limit treatment for patients with progressive ophthalmological symptoms.

Adolescent↗

Testicular disease in childhood B-cell non-Hodgkin's lymphoma: the French Society of Pediatric Oncology experience.

PURPOSE: To investigate whether testicular disease in childhood B-cell lymphoma should continue to be considered a sanctuary site, as it is with other lymphoid malignancies such as acute lymphoblastic leukemia. PATIENTS AND METHODS: Seven hundred forty-two children with B-cell non-Hodgkin's lymphoma were included in the LMB protocols of the French Society of Pediatric Oncology from February 1981 to May 1994. Thirty patients (5.3%) had testicular involvement at diagnosis. We describe the clinical presentation and outcome of these 30 patients, who were treated without local radiation therapy. RESULTS: Five patients underwent diagnostic orchidectomy. The median patient age was 8.5 years (range, 2 to 14 years), and their cancers were stage III (18 patients), stage IV (five patients), and B-cell acute lymphoblastic leukemia (seven patients). Five patients had central nervous system involvement. Twenty-eight patients (95%) achieved complete remission. Twenty-six patients are alive without progressive disease (median follow-up, 6.5 years). CONCLUSION: Testicular disease does not seem to confer a poor prognosis, and it is curable with intensive combination chemotherapy alone. Local treatment (surgery or radiation) is avoidable; therefore, gonadal function can be preserved.

Adolescent↗

Localised and unresectable neuroblastoma in infants: excellent outcome with primary chemotherapy. Neuroblastoma Study Group, Société Française d'Oncologie Pédiatrique.

PROCEDURE: Infants with neuroblastoma (NB) were assessed according to INSS recommendations, including MIBG scan and extensive bone marrow staging to eliminate metastatic spread. Patients with unresectable tumour received chemotherapy, including two courses of carboplatin-etoposide (CE) and two of vincristinecyclophosphamide-doxorubicin (CAdO). Post-operative treatment was to be given only in infants with MYCN amplification. Between 1990 and 1994, 52 consecutive children were registered. RESULTS: Among the 44 patients who received CE as a first course, the response rate was (66%) and the primary could be removed in all children but one, who was in remission. The toxicity was mainly haematological and was always manageable. The 5 year overall survival (OS) and event-free survival (EFS) were 94 and 90 +/- 8%, respectively, with a median follow-up of 48 months. The outcome of infants with no MYCN amplification was excellent; OS and EFS were, respectively, 97 and 94%. CONCLUSIONS: Chemotherapy allows surgical excision and excellent outcome in infants with localised and unresectable NB. Less intensive Chemotherapy should be investigated in such patients.

Antineoplastic Combined Chemotherapy Protocols↗

Comparison of nonlinear mixed-effect and non-parametric expectation maximisation modelling for Bayesian estimation of carboplatin clearance in children.

OBJECTIVE: The pharmacodynamic-pharmacokinetic relationships for carboplatin involve the area under the curve of ultrafiltrable plasma concentrations versus time (AUC). The objective of the study was to compare two specific population pharmacokinetic methodologies, nonlinear mixed-effect model (NONMEM) and non-parametric expectation maximisation (NPEM), when they are applied to sparse carboplatin pharmacokinetic data in order to obtain an individual value for carboplatin clearance by Bayesian estimation. METHODS: The data from 117 patients (from 1 month to 18 years old) were available. For 20 patients randomly selected, the carboplatin clearance obtained by Bayesian estimation using two plasma ultrafiltrable concentrations was compared with that obtained by individual analysis using all concentrations. RESULTS: Both methodologies were unbiased with mean relative percentage errors (95%CI) of -1.9% ( 7.8; +4.1%) and +6.4% (-2.1; +14.9%) for NONMEM and NPEM, respectively. A comparison of precision between the two methods showed that they were not significantly different (12.5% for NONMEM, and 18.9% for NPEM), but the percentage error ranged between -21% and + 19% for NONMEM, and -35% and + 42% for NPEM. A NONMEM analysis was also performed with all the data available (117 children) in order to update an equation describing the relationship between carboplatin clearance and the patients' covariates. The best relationship corresponded to the equation: clearance (ml/min) = [4.47 x body weight x (1 -0.22 x Np)/(l + 0.0156 x Scr)] +6.4, with body weight in kilograms and where Scr is serum creatinine in micromoles per litre and Np= 1 or 0 for unilateral nephrectomy or not, respectively. CONCLUSION: These methodologies may be useful for dose individualisation and drug monitoring of carboplatin in paediatric patients. Since the mode of administration of carboplatin in paediatric practice in some protocols is daily 1-h i.v. infusion repeated up to five times, dose individualisation may be performed from the clearance observed after the first administration, given an overall target AUC.

Adolescent↗